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Classifications

ICD-O Morphology

Harrison's Part

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Mappings

MONDO

MONDO:0005082 prostate adenocarcinoma

MONDO provides an exact disease term for prostate adenocarcinoma; this is the same term used as `disease_term` for this entry.

MONDO:0004956 metastatic prostate carcinoma Not Yet Curated

MONDO's dedicated metastatic prostate carcinoma entity corresponds to the Metastatic stage of this entry (the former Metastatic_Prostate_Cancer entry, folded in per design decisions §3a).

NCIT

NCIT:C2919 Prostate Adenocarcinoma

NCIT provides an exact concept for prostate adenocarcinoma; MONDO:0005082 cross-references NCIT:C2919 in its xref list.

NCIT

NCIT:C2919 Prostate Adenocarcinoma

NCIT provides an exact concept for prostate adenocarcinoma; MONDO:0005082 cross-references NCIT:C2919 in its xref list.

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Definitions

1

13-CMB AI morphometric predictor of neoadjuvant ADT response

A computable, image-derived predictor that classifies a prostate adenocarcinoma needle biopsy as a likely responder or non-responder to neoadjuvant androgen deprivation therapy (NADT) — the terminology used in the source publication. Inputs are the abundance levels of 13 cellular morphometric biomarkers (CMBs) — unsupervised, machine-learned cell-appearance prototypes extracted from H&E whole-slide images by the CMB-ML pipeline (stacked predictive sparse decomposition), NOT named histopathology findings — combined by a LASSO regression into a continuous treatment-resistance score that is dichotomized into responder versus non-responder. The predictor operationalizes the split that this entry's "Signaling Bypass and Castration Resistance" node captures: the non-responder state it flags converges on PI3K/AKT/mTORC1-hyperactive adaptive resistance (see conforms_to on that node, mtor_androgen_deprivation_resistance), which is why it also predicts potential benefit from adding an mTOR inhibitor in non-responders.

PHENOTYPE_ALGORITHM Research-grade, imaging-derived treatment-response predictor from routine H&E needle-biopsy whole-slide images. This is NOT an OHDSI/OMOP EHR case-finding query and NOT a consensus/validated clinical phenotype; it is a published AI biomarker validated retrospectively across independent cohorts. The 13 CMBs are latent learned features (cluster prototypes), so they are not individually ontology-mappable to NCIT histopathology terms; the biological correlates and the mTOR-resistance mechanism are what carry ontology grounding (on the pathophysiology nodes and the conformed module).

Show evidence (4 references)

PMID:41887393 SUPPORT Human Clinical

"we identified 13 cellular morphometric biomarkers (CMBs), as a New Approach Methodology (NAM), from whole slide images of needle biopsies in clinical trial specimens (NCT02430480, n = 37) that accurately predicted response to neoadjuvant androgen deprivation therapy (NADT) plus enzalutamide"

Establishes the 13-CMB LASSO model as an AI predictor of NADT response derived from H&E whole-slide images of needle biopsies in the trial cohort.

PMID:41887393 SUPPORT Human Clinical

"the 13-CMB model stratified PCa patients into responders and non-responders after NADT across two independent hospital cohorts."

Supports independent-cohort validation of the responder/non-responder stratification this definition operationalizes.

PMID:41887393 SUPPORT Human Clinical

"the 13-CMB model demonstrated significant and independent clinical value after adjustment for established clinical factors and commonly used genomic biomarkers, including Decipher and Oncotype DX."

Supports the claim that the predictor adds value independent of standard clinical factors and the Decipher/Oncotype DX genomic assays.

+ 1 more reference

Notes: Schema-fit caveat (design-register item): dismech's derivation_basis enum has no value for an empirically-derived AI/imaging predictor. ESTABLISHED_CRITERIA is used here under its "validated computable phenotype" clause because the model is a published, cohort-validated computable predictor; its research-grade, not-yet-gold-standard maturity is carried separately (and honestly) by validation_status: UNVALIDATED. definition_type PHENOTYPE_ALGORITHM is likewise the closest available bucket — the model is a computable predictive algorithm, but on H&E whole-slide-image features rather than OMOP/EHR case-finding logic, so it cannot be expressed as inline criteria_sets. Provenance: Yan et al., Cancer Letters 647 (2026) 218447, doi:10.1016/j.canlet.2026.218447, trial NCT02430480. A dedicated imaging/ML-biomarker definition_type and an EMPIRICAL_MODEL derivation_basis are proposed follow-ups for the design register.

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Discussions and Knowledge Gaps

2

Integrated mutational footprints stratify metastasis risk in primary prostate cancer and, in one footprint, separate men who fail later on an AR pathway inhibitor than on a taxane. Both results come from retrospective cohorts - the treatment result from a target trial emulation over real-world metastatic whole-genome data with small subgroups. Does an integrated footprint add risk or treatment-selection information beyond Gleason grade group, stage, tumour mutational burden and the single-gene biomarkers already in use, when measured prospectively?

KNOWLEDGE GAP OPEN kg_prostate_integrated_mutational_footprint_biomarker_validation

Attached to

pathophysiology#Replication Stress-Driven Chromosomal Instability pathophysiology#Reactive Oxygen Species-Driven Mutagenesis pathophysiology#CDK12-Associated Non-Canonical Homologous Recombination Impairment pathophysiology#Homologous Recombination Deficiency treatments#Androgen Deprivation plus AR Pathway Inhibition

The gap is not whether these mutational processes exist - the footprints are derived from whole-genome data and each carries a driver-gene and signature-level aetiology, which is why they are curated as mechanism nodes in this entry. It is whether they are usable. Two of the claims that would matter clinically rest on designs that cannot settle the question. The metastasis-risk associations are from a multivariate model on an observational cohort, so they establish independence from the recorded covariates rather than incremental value over the decision rule a clinician actually applies. The treatment-selection result is a trial emulation, and its authors are explicit that it is hypothesis generating with limited subgroup sizes; only seven patients in that cohort carried the single-gene alteration the footprint is thought to generalize. There is also an ascertainment asymmetry worth stating: the footprints were defined on tumours with chromosomal instability and quantified in whole-genome sequencing, so a prospective test has to specify how a tumour with low purity, low variant burden, or targeted-panel-only sequencing is classified, since roughly a sixth of the discovery cohort could not be assigned any mutational process at all.

Show evidence (2 references)

PMID:42717097 SUPPORT Human Clinical

"As our trial emulation analyses are retrospective and observational, with limited subgroup sizes, these findings should be viewed as hypothesis generating"

The authors' own characterization of the treatment-selection result as hypothesis generating is the basis for curating this as an open gap rather than as a predictive biomarker.

PMID:42717097 SUPPORT Human Clinical

"we showed that IMF6 activity was predictive of reduced risk of treatment failure following ARPI"

States the treatment-selection finding whose prospective confirmation this gap asks for.

In mice, gut commensals expand under androgen deprivation and supply an alternative source of active androgens: antibiotic ablation of the gut microbiota delays the emergence of castration resistance, and fecal transplant from castration-resistant donors confers it. In humans the same axis is so far only an association - the intestinal community of patients with castration-resistant prostate cancer is enriched for androgen-converting species, with no interventional human evidence. Does microbial androgen biosynthesis contribute to castration resistance in human prostate cancer, or is the mouse dependency amplified by a host in which adrenal androgen production is negligible?

HUMAN MODEL MISMATCH OPEN hmm_prostate_microbial_androgen_biosynthesis_castration_resistance

Attached to

pathophysiology#Androgen Receptor Signaling Dependence pathophysiology#Signaling Bypass and Castration Resistance treatments#Androgen Deprivation Therapy

This entry curates castration resistance as a tumor-intrinsic bypass - AR amplification, AR splice variants, and intratumoral steroidogenesis. The mouse evidence adds a host-external route the pathograph does not represent: the gut community itself converting circulating androgen precursors into active androgens, restoring ligand to the receptor the therapy was meant to starve. What keeps this from being curated as a mechanism node is a species difference that is mechanistically load-bearing rather than incidental. Mice produce little adrenal androgen, so a microbial precursor-conversion route faces little host competition there; in castrated men, adrenal DHEA and androstenedione remain a substantial precursor pool that intratumoral steroidogenesis already exploits, which is the rationale for abiraterone. A microbial contribution in humans therefore has to be shown to be non-redundant with a pathway this entry already models, not merely present. The human data reported alongside the mouse experiments are observational, and the cross-disease review that prompted this discussion still describes microbial metabolism of host hormonal precursors as hypothesized rather than established for endocrine-therapy resistance. Until a human intervention separates the two sources, an edge from a microbial node into castration resistance would assert translational validity that the evidence does not yet carry.

Proposed experiments

Human test of whether gut microbial androgen conversion is non-redundant with adrenal precursor supply

randomized microbiota-directed intervention nested in a prospective cohort

exp_prostate_microbial_androgen_conversion_human_intervention

In men starting androgen deprivation therapy, serially profile the fecal metagenome for androgen-converting gene content alongside serum and fecal steroid metabolomics, and test whether microbial conversion capacity predicts time to castration resistance independently of adrenal precursor levels. Nest a randomized microbiota-directed intervention (a narrow-spectrum antimicrobial or defined live biotherapeutic selected against the converting taxa) within the cohort, stratified by baseline adrenal androgen level, so that a microbial effect can be distinguished from the adrenal-precursor route that abiraterone already targets.

Readouts

Microbial androgen-conversion capacity and time to castration resistance

pathophysiology#Signaling Bypass and Castration Resistance

Association between baseline and on-treatment fecal androgen-converting gene content and time to biochemical castration resistance, adjusted for serum adrenal androgen precursors.

shotgun metagenomic sequencing targeted steroid mass spectrometry

Circulating active androgen after microbiota-directed intervention

pathophysiology#Androgen Receptor Signaling Dependence

Change in serum testosterone and dihydrotestosterone in the intervention arm relative to control, within adrenal-androgen strata.

targeted steroid mass spectrometry

Direction: DECREASED

Decision criterion

Translational validity is supported if microbial androgen-conversion capacity predicts earlier castration resistance independently of adrenal precursor levels AND the microbiota-directed intervention lowers active androgen and delays resistance in men with low adrenal androgen output. It is not supported if the association disappears after adjustment for adrenal precursors, or if the intervention alters community composition without changing androgen levels or outcome - in which case the mouse result should stay flagged as model-specific.

Would support

pathophysiology#Signaling Bypass and Castration Resistance

Recorded from monarch-initiative/dismech#6383. Typed HUMAN_MODEL_MISMATCH rather than KNOWLEDGE_GAP because the evidence is not absent - it is strong and causal in mice, and the open question is whether it transfers to human castration resistance. The PMID:42426614 item carries `evidence_source: OTHER` because that publication is a narrative review making a field-level synthesis claim rather than reporting primary data; see monarch-initiative/dismech#8184.

Show evidence (4 references)

PMID:34618582 SUPPORT Model Organism

"Ablation of the gut microbiota by antibiotic therapy delayed the emergence of castration resistance even in immunodeficient mice."

The causal arm of the claim, and it is entirely murine: removing the microbiota changes the timing of castration resistance in mice.

PMID:34618582 SUPPORT Model Organism

"Fecal microbiota transplantation (FMT) from CRPC mice and patients rendered mice harboring prostate cancer resistant to castration."

Transfer experiment establishing sufficiency - but the readout organism is the mouse, including for the human-donor material, so it does not close the translational question.

PMID:34618582 SUPPORT Human Clinical

"Specifically, the intestinal microbial community in mice and patients with CRPC was enriched for species capable of converting androgen precursors into active androgens."

The human arm of the finding. The quoted sentence spans both mouse and patient cohorts and is tagged here for its human component, which is observational enrichment only - no human intervention was performed.

+ 1 more reference

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Pathophysiology

16

Androgen Receptor Signaling Dependence

Prostate adenocarcinoma is organized around androgen receptor (AR) signaling, which sustains lineage identity, proliferation, and survival and therefore remains the dominant therapeutic dependency across much of the disease course.

epithelial cell of prostate CL:0002231

androgen receptor signaling pathway GO:0030521 ↑ INCREASED

prostate gland UBERON:0002367

Downstream

Lipogenic Metabolic Reprogramming AR activation promotes anabolic lipid metabolism that supports tumor growth.

Signaling Bypass and Castration Resistance Treatment pressure selects AR-reactivated and AR-bypass states.

TMPRSS2:ERG Fusion-Driven ETS Activation Androgen-responsive TMPRSS2 promoter elements drive aberrant ERG overexpression in the roughly half of tumors carrying the fusion.

AR-Mediated Mutagenesis at Androgen Receptor Binding Sites Sustained AR occupancy is itself mutagenic, raising the local mutation rate and concentrating chained rearrangements at tumor-specific AR binding sites.

Show evidence (1 reference)

PMID:34771580 SUPPORT

"Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR)."

The abstract identifies AR as the central mechanistic axis that has driven therapy development in prostate cancer.

TMPRSS2:ERG Fusion-Driven ETS Activation

In approximately half of prostate adenocarcinomas an androgen-responsive TMPRSS2 promoter is fused to the ETS transcription factor ERG, placing ERG under androgen control and driving its aberrant overexpression. The resulting ETS transcriptional program promotes an invasion-associated, less-differentiated phenotype and defines the predominant molecular subtype of the disease.

epithelial cell of prostate CL:0002231

Genetic context variant_origin: SOMATIC

ETS (ERG) target gene transcriptional activation GO:0045944 ↑ INCREASED

prostate gland UBERON:0002367

Downstream

Epithelial-Mesenchymal Transition ERG-driven invasion-associated transcriptional reprogramming promotes the invasive cellular phenotype that precedes distant spread.

Show evidence (3 references)

PMID:16254181 SUPPORT Human Clinical

"we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1"

Fluorescence in situ hybridization in human prostate cancer tissue established recurrent ERG/ETV1 rearrangements as a frequent somatic event.

PMID:16254181 SUPPORT In Vitro

"Cell line experiments suggest that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer."

This identifies the androgen-driven TMPRSS2 promoter as the mechanism placing ETS factors such as ERG under aberrant transcriptional control.

PMID:18283340 SUPPORT In Vitro

"Introduction of the ERG gene fusion product into primary or immortalized benign prostate epithelial cells induced an invasion-associated transcriptional program but did not increase cellular proliferation or anchorage-independent growth."

Functional introduction of the ERG fusion product activates an invasion-associated transcriptional program, indicating the fusion contributes to invasion rather than proliferation.

Lipogenic Metabolic Reprogramming

Prostate adenocarcinoma shows unusually strong dependence on de novo fatty acid synthesis, an AR-linked metabolic program that supports membrane biogenesis, signaling, and aggressive tumor behavior.

fatty acid biosynthetic process GO:0006633 ↑ INCREASED

Show evidence (1 reference)

PMID:34145040 SUPPORT

"Prostate cancer exhibits unique metabolism with high rates of de novo fatty acid synthesis driven by activation of the androgen receptor (AR)."

This directly supports AR-driven lipogenic reprogramming as a core metabolic feature of prostate cancer.

Signaling Bypass and Castration Resistance

As disease progresses under androgen deprivation, resistant clones emerge through AR splice variants, AR overexpression or mutation, and activation of PI3K/AKT and other compensatory pathways that restore growth despite ARSI therapy. This node conforms to the mtor_androgen_deprivation_resistance module: AR-pathway blockade relieves feedback inhibition of the PI3K/AKT axis (potentiated by PTEN loss in this disease), driving compensatory mTORC1 hyperactivation that sustains survival under androgen blockade — the biological basis for the co-targeting (mTOR-inhibitor plus ARPI) therapeutic rationale.

phosphatidylinositol 3-kinase/protein kinase B signal transduction GO:0043491 ↑ INCREASED TORC1 Signaling GO:0038202 ↑ INCREASED

Downstream

Epithelial-Mesenchymal Transition Resistant signaling states promote invasive cellular reprogramming that precedes distant spread.

Clonal Evolution and Lineage Plasticity Treatment pressure selects resistant subclones and alternative cell states.

Show evidence (3 references)

PMID:34771580 SUPPORT

"DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins."

This abstract sentence directly describes the bypass pathways that support AR-independent or incompletely AR-dependent progression.

PMID:21575859 SUPPORT Model Organism

"Similarly, AR inhibition activates AKT signaling by reducing levels of the AKT phosphatase PHLPP. Thus, these two oncogenic pathways cross-regulate each other by reciprocal feedback. Inhibition of one activates the other, thereby maintaining tumor cell survival."

Demonstrates the reciprocal AR-PI3K/AKT feedback in prostate cancer models that converts AR blockade into compensatory PI3K/AKT (and downstream mTORC1) activation; folded in from the former Metastatic_Prostate_Cancer entry.

PMID:30535926 SUPPORT Human Clinical

"Oral enzalutamide (Xtandi®), a second generation androgen receptor inhibitor, is indicated for the treatment of castration-resistant prostate cancer (CRPC) in numerous countries worldwide, with specific indications in this patient population varying between individual countries."

Supports the continued centrality of AR signaling in metastatic castration-resistant disease.

Epithelial-Mesenchymal Transition

Progression from organ-confined adenocarcinoma toward invasive disease involves signaling networks that promote epithelial-to-mesenchymal transition and increased migratory capacity.

epithelial to mesenchymal transition GO:0001837 ↑ INCREASED

Downstream

Metastatic Dissemination EMT-like reprogramming supports invasion and subsequent distant spread.

Show evidence (1 reference)

PMID:40372974 SUPPORT

"Particular pathways that allow cells to proliferate by creating a network of new blood vessels have been documented, whereas other pathways are primarily involved with a migration to distant body parts, partially through the process of epithelial-mesenchymal transition (EMT)."

This review abstract explicitly links prostate cancer progression and distant spread to EMT-related signaling pathways.

Metastatic Dissemination

Advanced prostate adenocarcinoma can disseminate beyond the prostate to distant metastatic sites as disease progresses or recurs after definitive local therapy.

Downstream

Osteoblastic Bone Tropism Disseminated prostate cancer cells preferentially colonize bone, where tumor-stromal signaling produces the characteristic osteoblastic lesions.

Show evidence (1 reference)

PMID:40063046 SUPPORT

"Despite definitive therapy, 2% to 56% of men with localized disease develop distant metastases, depending on tumor risk factors."

This directly supports progression from initially localized prostate cancer to distant metastatic dissemination.

Immune-Suppressive Tumor Microenvironment

Prostate adenocarcinoma typically has a relatively immunologically cold microenvironment with weak endogenous antitumor activity, contributing to the limited single-agent activity of checkpoint immunotherapy in unselected disease.

negative regulation of immune response GO:0050777 ↑ INCREASED

Show evidence (1 reference)

PMID:33106940 SUPPORT

"Tumor progression and patient outcomes depend on complex cellular and molecular interactions of the tumor with the host immune system, driven rather dormant in case of PCa."

This supports the relatively dormant immune contexture of prostate cancer and the importance of tumor-immune interactions.

Osteoblastic Bone Tropism

Bone is the dominant metastatic niche in prostate cancer. Tumor-stromal signaling stimulates abnormal woven bone formation and couples osteoblastic and osteolytic remodeling, producing fragile but radiographically dense skeletal lesions.

positive regulation of ossification GO:0045778 ↑ INCREASED

Show evidence (1 reference)

PMID:18639279 SUPPORT Human Clinical

"In contrast with metastases caused by other carcinomas such as breast, thyroid, kidney, and lung that destroy bone and are termed “osteolytic,” prostate cancer generally causes a bone-forming or “osteoblastic” response."

This directly supports the osteoblastic bone tropism that distinguishes metastatic prostate cancer.

Clonal Evolution and Lineage Plasticity

Under treatment pressure, metastatic prostate cancer accumulates resistant subclones and can adopt alternative lineage states that support persistence after AR-targeted therapy.

cell fate commitment GO:0045165 ⚠ ABNORMAL

AR-Mediated Mutagenesis at Androgen Receptor Binding Sites

Androgen receptor binding is a mutagenic event and not only a transcriptional one. Whole-genome analysis of the Pan Prostate Cancer Group cohort identifies AR-mediated mutagenesis as the most recurrent integrated mutational footprint in chromosomally unstable primary tumors, raising the local mutation rate at tumor-specific AR binding sites (TARBSs) and concentrating chromoplexy - chains of interchromosomal complex rearrangements - specifically and uniquely at those sites. Chromoplexy is an established generator of ERG fusions, and it is concentrated at AR binding sites, so this process is the most likely origin of the androgen-driven fusion events this entry already models - but the step that AR binding is what localizes the chromoplexy remains an inference from co-localization, not a demonstrated one. Its intensity tracks the epigenetic state of the site rather than AR occupancy alone: TARBSs are enriched for unmethylated CpGs, which places the process in early-replicating, transcriptionally active chromatin and accounts for the local depletion of the 5-methylcytosine-deamination signature SBS1 there.

epithelial cell of prostate CL:0002231

androgen receptor signaling pathway GO:0030521 ↑ INCREASED chromoplexy (chained interchromosomal rearrangement) at AR binding sites GO:0006310 ↑ INCREASED

prostate gland UBERON:0002367

Downstream

TMPRSS2:ERG Fusion-Driven ETS Activation Chromoplexy generates ERG fusions and precedes them in the clonal ordering, and chromoplexy is specifically enriched at tumor-specific AR binding sites. The edge therefore runs generation-then-expression: this node makes the rearrangement, the AR-dependency node transcribes through it.

Clonal Evolution and Lineage Plasticity Recurrent AR-directed rearrangement adds heritable structural diversity for selection to act on.

Metastatic Dissemination Tumors dominated by AR-mediated mutagenesis reached metastasis sooner than chromosomally stable tumors in the PPCG cohort.

Show evidence (4 references)

PMID:42717097 SUPPORT Human Clinical

"IMFs were strongly influenced by regional biases in the genome, most prevalently androgen receptor-mediated mutagenesis and replication stress."

Identifies AR-mediated mutagenesis as one of the two dominant regional influences shaping mutational processes across primary prostate cancer genomes, which is the claim this node makes.

PMID:42717097 SUPPORT Human Clinical

"We found chromoplexy events to be specifically and uniquely enriched at tumour-specific ARBSs"

Establishes the structural-variant class this node attributes to AR binding, and that the enrichment is specific to tumor-specific binding sites rather than to AR binding in general.

PMID:42717097 SUPPORT Human Clinical

"This suggests that the AR mutagenicity at enhancers and promoters is conditioned on existing CpG methylation levels."

Supports the conditioning of AR mutagenicity on the local methylation state, which is why this node treats the epigenetic context as part of the mechanism rather than as background.

+ 1 more reference

Replication Stress-Driven Chromosomal Instability

Dysfunctional DNA replication is the dominant mutational process in roughly a quarter of chromosomally unstable primary prostate cancers, resolving into two integrated footprints: one combining mitotic-machinery defects with replication stress, and one linked to SPOP and WNT-pathway alterations. Faulty replicated DNA persisting into mitosis yields copy-number and complex structural change rather than a distinctive base-substitution spectrum, which is why the process was only resolved by integrating substitution, indel, copy-number and complex structural-variant signatures. Clinically this footprint separates from the metastasis-associated processes in two ways: it predominates in late-onset disease, and higher activity of the SPOP-associated footprint marked tumors that failed later on AR pathway inhibitors than on taxanes.

epithelial cell of prostate CL:0002231

DNA replication under replication stress GO:0006260 ⚠ ABNORMAL chromosome organization GO:0051276 ⚠ ABNORMAL

Downstream

Clonal Evolution and Lineage Plasticity Copy-number and structural change generated by unresolved replication stress expands the subclonal repertoire available to treatment selection.

Show evidence (4 references)

PMID:42717097 SUPPORT Human Clinical

"Our study also identified a pervasive role for replication stress in prostate cancer, with dysfunctional DNA replication as the dominant mutational process in 28% of prostate cancers with CIN"

Quantifies the share of chromosomally unstable primary tumors in which replication stress is the dominant mutational process, the central claim of this node.

PMID:42717097 SUPPORT Human Clinical

"suggesting faulty replicated DNA after replication stress that persists into mitotic defects"

States the mechanistic link this node models between replication stress and the mitotic-defect footprint, rather than treating the two as separate processes.

PMID:42717097 SUPPORT Human Clinical

"IMF6 exhibited increased activity in cases with mutations in SPOP and WNT-pathway genes APC and SOX17"

Provides the driver-gene association behind the SPOP-linked replication-stress footprint named in this node's description.

+ 1 more reference

Reactive Oxygen Species-Driven Mutagenesis

A distinct integrated footprint attributes part of the mutation burden to oxidative DNA damage handled by a faulty base-excision repair pathway, marked by the substitution signature SBS18 and concentrated in late-replicating regions. It is anti-correlated with tumor hypoxia score, so it reads as an oxygen-dependent damage process rather than as a consequence of the hypoxic niche. Among the footprints that carry prognostic weight, this is one of the four associated with shorter time to metastasis, which makes oxidative mutagenesis a candidate risk axis independent of Gleason grade group and tumor mutational burden.

epithelial cell of prostate CL:0002231

response to oxidative stress GO:0006979 ↑ INCREASED base-excision repair GO:0006284 ↓ DECREASED

Downstream

Metastatic Dissemination Tumors dominated by oxidative mutagenesis progressed to metastasis sooner than chromosomally stable tumors, independent of grade, stage and mutational burden.

Clonal Evolution and Lineage Plasticity Unrepaired oxidative lesions raise the substitution burden feeding subclonal diversification.

Show evidence (3 references)

PMID:42717097 SUPPORT Human Clinical

"IMF2 (ROS mutagenesis) was significantly associated with SBS18"

Ties the footprint this node curates to its defining base-substitution signature.

PMID:42717097 SUPPORT Human Clinical

"a signature linked with faulty BER and DNA damage induced by ROS"

Gives the aetiology assigned to that signature - reactive-oxygen-species damage repaired through a defective base-excision pathway - which is the mechanism this node models.

PMID:42717097 SUPPORT Human Clinical

"Four IMFs, present in 37% of primary tumours, were significantly associated with shorter time to metastasis."

Establishes that a defined subset of these mutational processes, this one among them, carries prognostic weight for metastasis in primary disease.

Homologous Recombination Deficiency

Canonical homologous-recombination deficiency is the therapeutically actionable caretaker defect in prostate cancer and the footprint most closely tied to BRCA2 alteration, combining the substitution signature SBS3, the microhomology-mediated deletion signature ID6, and complex structural and copy-number signatures of impaired repair. It is uncommon in primary disease - fewer than 3% of primary tumors - but is enriched in early-onset cases and is one of the four footprints associated with shorter time to metastasis. This is the mechanism the entry's PARP-inhibitor combination treatment is directed at.

epithelial cell of prostate CL:0002231

double-strand break repair via homologous recombination GO:0000724 ↓ DECREASED

Downstream

Metastatic Dissemination Homologous-recombination-deficient primary tumors carried a high risk of progression to metastasis relative to chromosomally stable tumors.

Clonal Evolution and Lineage Plasticity Loss of accurate double-strand break repair drives the structural diversification on which subclonal selection acts.

Show evidence (3 references)

PMID:42717097 SUPPORT Human Clinical

"IMF8 (impaired HR) was correlated with mutational signatures SBS3, ID6, cSV6 and CX3 related to impaired HR"

Names the multi-modality signature combination that defines this footprint, which is the basis for treating it as a single mechanism rather than as several independent signatures.

PMID:42717097 SUPPORT Human Clinical

"IMF8 activity was also significantly higher in cases with BRCA2 mutations"

Supplies the driver-gene association that assigns a canonical homologous-recombination aetiology to this footprint.

PMID:42717097 SUPPORT Human Clinical

"fewer than 3% of primary prostate cancers exhibit a deficiency in this repair mechanism"

Quantifies how rare canonical homologous-recombination deficiency is in primary disease, which is the reason this node is curated alongside, rather than in place of, the other mutational processes.

CDK12-Associated Non-Canonical Homologous Recombination Impairment

A second impaired-homologous-recombination footprint is separable from the canonical BRCA-driven one by both its driver and its damage pattern. It is associated with CDK12 mutation, which phenocopies impaired homologous recombination without BRCA1/2 loss, and its structural signature is dominated by tandem duplications rather than by microhomology-mediated deletion. It is enriched in patients of African ancestry and confers a high risk of progression to metastasis. Curating it separately matters clinically, because a tumor can carry a homologous-recombination-like footprint while being negative for the BRCA alterations that current PARP-inhibitor eligibility is written around.

epithelial cell of prostate CL:0002231

double-strand break repair via homologous recombination GO:0000724 ↓ DECREASED tandem duplication formation GO:0006310 ↑ INCREASED

Downstream

Metastatic Dissemination Tumors dominated by this footprint showed the highest hazard of progression to metastasis among the dominant mutational processes assessed.

Clonal Evolution and Lineage Plasticity A tandem-duplicator genome generates recurrent copy gain across many loci, broadening the substrate for selection.

Show evidence (4 references)

PMID:42717097 SUPPORT Human Clinical

"IMF5 (non-canonical impaired HR) had significantly higher activity in tumours with mutations in CDK12"

Provides the driver association that separates this footprint from the canonical BRCA2-associated one curated above.

PMID:42717097 SUPPORT Human Clinical

"which has been shown to phenocopy impaired HR in the absence of mutations in BRCA1/2"

States the mechanistic basis for calling this a homologous-recombination impairment despite intact BRCA1/2, which is what makes it non-canonical.

PMID:42717097 SUPPORT Human Clinical

"IMF5 activities were significantly correlated with cSV4, characterized by tandem duplications"

Gives the distinctive structural-variant pattern - a tandem-duplicator phenotype - that distinguishes this footprint from canonical homologous-recombination deficiency.

+ 1 more reference

Mismatch Repair Deficiency and Microsatellite Instability

Loss of DNA mismatch repair, most often through MSH2 alteration, produces the replicative-slippage footprint that combines the MMR-associated substitution signatures with the characteristic indel signature, and yields microsatellite instability. Its topographical behaviour is diagnostic: where the other mutational processes are strongly biased by replication timing and chromatin state, mismatch-repair-deficient tumors mutate at a near-uniform rate across the genome, consistent with replication-coupled repair normally being most efficient in early-replicating regions. Unlike the other footprints curated here it is also detectable in chromosomally stable tumors. This is the mechanism behind the entry's biomarker-selected checkpoint-blockade indication.

epithelial cell of prostate CL:0002231

mismatch repair GO:0006298 ↓ DECREASED

Downstream

Immune-Suppressive Tumor Microenvironment The hypermutated, microsatellite-unstable genome raises neoantigen load, which is the basis for biomarker-selected checkpoint blockade in this subset.

Clonal Evolution and Lineage Plasticity An elevated, uniformly distributed substitution and indel rate accelerates subclonal diversification.

Show evidence (4 references)

PMID:42717097 SUPPORT Human Clinical

"IMF1 (MMRd) activity correlated with MMRd-related mutational signatures SBS15, SBS21 and ID2"

Ties this footprint to the mismatch-repair signature set that defines it.

PMID:42717097 SUPPORT Human Clinical

"IMF1 had higher activity in cases with microsatellite instability"

Connects the footprint to the microsatellite-instability phenotype that this node names and that the entry's checkpoint-blockade indication is written around.

PMID:42717097 SUPPORT Human Clinical

"Tumours with high IMF1 exhibited a near-uniform mutation rate across the genome"

Supports the distinguishing topographical property recorded in this node's description - absence of the regional bias seen in the other footprints.

+ 1 more reference

APOBEC Cytidine Deaminase Mutagenesis

APOBEC-family cytidine deaminase activity contributes a separate footprint carrying the APOBEC substitution signatures. Its regional behaviour links it to structural catastrophe rather than to replication timing: APOBEC-signature mutations cluster around complex structural-variant breakpoints, consistent with single-stranded DNA exposed during chromothripsis being edited by the deaminase. Clonality analysis places APOBEC mutations early in tumor evolution while the impaired-recombination signatures accompanying this footprint appear subclonally, which is the argument for reading APOBEC editing as the driving aetiology here and the recombination signatures as a later, separate process.

epithelial cell of prostate CL:0002231

APOBEC3 cytidine deaminase activity on single-stranded DNA GO:0004126 ↑ INCREASED

Downstream

Clonal Evolution and Lineage Plasticity Clonal APOBEC editing establishes an early substitution burden on which later selection operates.

Show evidence (3 references)

PMID:42717097 SUPPORT Human Clinical

"IMF7 (APOBEC mutagenesis) was correlated with APOBEC-associated signatures SBS2 and SBS13"

Ties this footprint to the cytidine-deaminase substitution signatures that define it.

PMID:42717097 SUPPORT Human Clinical

"suggesting APOBEC-mediated editing at chromothriptic breakpoints"

Supports the spatial coupling between APOBEC editing and complex structural-variant breakpoints that this node models.

PMID:42717097 SUPPORT Human Clinical

"We found that APOBEC-related mutations often occurred clonally, while impaired HR mutations appeared subclonally"

Provides the timing argument for assigning APOBEC activity, rather than impaired recombination, as this footprint's aetiology.

✶

Histopathology

1

Acinar Adenocarcinoma

Classic acinar adenocarcinoma is the dominant morphologic pattern in prostate adenocarcinoma and the reference point against which less common glandular and non-glandular variants are compared.

Show evidence (1 reference)

PMID:36081403 SUPPORT

"The most common prostatic cancers (PCa) are acinary adenocarcinomas."

This directly supports acinar adenocarcinoma as the dominant histology among prostate cancers.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

6

Genitourinary 1

Hematuria HP:0000790

Show evidence (1 reference)

PMID:41134363 SUPPORT Human Clinical

"Prostatic artery embolization (PAE) has emerged as a minimally invasive option for the palliative control of hematuria in locally advanced or metastatic prostate cancer."

This supports hematuria as a clinically significant manifestation of locally advanced or metastatic prostate cancer.

Musculoskeletal 1

Recurrent fractures OCCASIONAL HP:0002757

Constitutional 3

Bone Pain HP:0002653

Show evidence (1 reference)

PMID:39169855 SUPPORT Human Clinical

"Prostate cancer metastasizes most commonly to the skeleton thus leading to significant morbidity ranging from pain, pathological fractures to spinal cord compression and are the primary cause of patient disability and reduced quality of life."

This supports bone pain as a characteristic morbidity of skeletal metastasis in prostate cancer.

Fatigue HP:0012378

Show evidence (1 reference)

PMID:39761938 SUPPORT Human Clinical

"PARPi therapies increased the incidence of adverse events (AEs), including fatigue, nausea, anemia, neutropenia, and thrombocytopenia."

This supports fatigue (alongside anemia) as a systemic therapy effect in prostate cancer, consistent with fatigue as a treatment-related manifestation.

Back pain FREQUENT HP:0003418

Other 1

Lower Urinary Tract Symptoms

Composite LUTS phenotype spanning urinary frequency, nocturia, hesitancy, and dysuria; no single precise HPO term is assigned here.

Show evidence (1 reference)

PMID:42074717 SUPPORT Human Clinical

"Lower urinary tract symptoms (LUTSs) are among the most common urological complaints in older men, frequently arising from benign prostatic hyperplasia (BPH) or prostate cancer (PCa)."

This supports lower urinary tract symptoms as a common presenting complaint that can arise from prostate cancer.

🧬

Genetic Associations

6

TMPRSS2:ERG (Somatic fusion-driven ETS activation)

Show evidence (1 reference)

PMID:40165885 SUPPORT

"Prostate cancer can be categorised into various risk groups of tumour molecular subtypes grounded in the idea of genomic structural variations connected to TMPRSS2:ERG fusion and loss of PTEN."

This directly links TMPRSS2:ERG fusion to prostate cancer molecular subtypes.

PTEN (Somatic loss or deletion)

Gene: PTEN hgnc:9588 gene page

Show evidence (1 reference)

PMID:29308088 SUPPORT Computational

"PTEN homozygous deletions had a significant increase in aneuploidy compared to PTEN tumors without an apparent deletion, and hemizygous deletions showed an intermediate aneuploidy profile."

This supports PTEN loss as a biologically consequential event associated with chromosomal instability in prostate cancer.

AR (Amplification, activating mutation, or splice variant expression during progression)

Gene: AR hgnc:644 gene page

Show evidence (1 reference)

PMID:34771580 SUPPORT

"Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR."

This abstract sentence directly supports AR reactivation through amplification, mutation, and splice variants in progressive disease.

TP53 (Somatic loss of function)

Gene: TP53 hgnc:11998 gene page

RB1 (Somatic loss of function)

Gene: RB1 hgnc:9884 gene page

MITF (Gain-of-function E318K mutation)

Gene: MITF hgnc:7105 gene page

Show evidence (1 reference)

PMID:42220083 SUPPORT Human Clinical

"We report the first case of metastatic prostate adenocarcinoma harboring a gain-of-function MITF E318K mutation. The patient presented with high tumor burden, rapid progression, and evidence of tumor heterogeneity. The E318K mutation, previously linked to melanoma and renal cell carcinoma,..."

First documented case of MITF E318K gain-of-function mutation in metastatic prostate cancer, expanding understanding of MITF's role in aggressive prostate cancer variants.

💊

Medical Actions

8

Radical Prostatectomy

Action: surgical procedure Ontology label: Surgical Procedure NCIT:C15329

Platform: Surgery

Surgical resection is a standard definitive option for higher-risk localized disease.

Show evidence (1 reference)

PMID:40063046 SUPPORT

"For patients with higher-risk disease, radiation therapy or radical prostatectomy are reasonable options"

This directly supports radical prostatectomy as a standard treatment option for localized higher-risk disease.

Radiation Therapy

Action: Radiation Therapy NCIT:C15313

Platform: Radiotherapy

External beam or related radiation approaches are standard definitive therapy for localized disease.

Show evidence (1 reference)

PMID:40063046 SUPPORT

"For patients with higher-risk disease, radiation therapy or radical prostatectomy are reasonable options"

The abstract explicitly names radiation therapy as a standard option for higher-risk localized disease.

Androgen Deprivation Therapy

Action: androgen deprivation therapy Ontology label: Hormone Therapy NCIT:C15445

Medical castration with gonadotropin-releasing hormone pathway suppression is the backbone of systemic therapy for metastatic hormone-sensitive disease.

Show evidence (1 reference)

PMID:40063046 SUPPORT

"Treatment of metastatic prostate cancer primarily relies on androgen deprivation therapy, most commonly through medical castration with gonadotropin-releasing hormone agonists."

This identifies androgen deprivation as the core systemic therapy backbone in metastatic disease.

Abiraterone Acetate

Action: Pharmacotherapy NCIT:C15986

Agent: abiraterone CHEBI:68642

CYP17-mediated androgen synthesis inhibition improves survival in metastatic castration-resistant prostate adenocarcinoma and is also used earlier in metastatic disease.

Show evidence (1 reference)

PMID:21612468 SUPPORT

"After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001)."

This pivotal trial abstract demonstrates an overall survival benefit for abiraterone in metastatic castration-resistant disease.

Enzalutamide

Action: Pharmacotherapy NCIT:C15986

Agent: enzalutamide NCIT:C71744

Second-generation androgen receptor inhibition is effective across nonmetastatic and metastatic castration-resistant settings.

Show evidence (2 references)

NCIT:C71744 SUPPORT Other

"Enzalutamide | Accepted_Therapeutic_Use_For | - | - | castration-resistant prostate cancer (CRPC)"

NCI Thesaurus asserts accepted therapeutic use of enzalutamide for castration-resistant prostate cancer.

PMID:30535926 SUPPORT

"Oral enzalutamide (Xtandi®), a second generation androgen receptor inhibitor, is indicated for the treatment of castration-resistant prostate cancer (CRPC) in numerous countries worldwide, with specific indications in this patient population varying between individual countries."

This supports enzalutamide as a standard AR-directed therapy for castration-resistant prostate cancer.

Androgen Deprivation plus AR Pathway Inhibition

Action: hormone modifying therapy Ontology label: Hormone Therapy NCIT:C15445

Agent: abiraterone CHEBI:68642 enzalutamide CHEBI:68534

Combination systemic therapy pairs androgen deprivation therapy with an androgen receptor pathway inhibitor for metastatic hormone-sensitive prostate cancer, replacing ADT monotherapy for many fit patients.

Mechanism Target:

INHIBITS Androgen Receptor Signaling Dependence — ADT and AR pathway inhibitors suppress the androgen receptor axis that remains a central growth dependency in metastatic prostate cancer.

Show evidence (1 reference)

DOI:10.1200/op-24-00690 SUPPORT Human Clinical

"Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with robust clinical trial evidence on the benefits of combining androgen-deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs; abiraterone, apalutamide, darolutamide, and enzalutamide) and/or..."

Supports combined ADT plus AR pathway inhibition as the systemic therapy directed at the persistent androgen-receptor-signaling dependency.

Show evidence (2 references)

DOI:10.1200/op-24-00690 SUPPORT Human Clinical

"Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with robust clinical trial evidence on the benefits of combining androgen-deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs; abiraterone, apalutamide, darolutamide, and enzalutamide) and/or..."

This supports ADT intensification with androgen receptor pathway inhibitors as a core systemic treatment pattern in mHSPC.

PMID:40315400 SUPPORT Other

"poly(ADP-ribose) polymerase inhibitors (PARPi), chemotherapeutic agents (docetaxel, cabazitaxel)"

The 2025 ASCO mCRPC guideline update lists the systemic therapy classes for metastatic castration-resistant prostate cancer, complementing the AR pathway inhibitors named here.

Talazoparib plus Enzalutamide

Action: targeted therapy Ontology label: Targeted Therapy NCIT:C93352

Agent: talazoparib CHEBI:231344 enzalutamide CHEBI:68534

PARP inhibitor and androgen receptor inhibitor combination therapy for homologous recombination repair gene-mutated metastatic castration-resistant prostate cancer.

Mechanism Target:

INHIBITS Androgen Receptor Signaling Dependence — Enzalutamide inhibits AR signaling while talazoparib targets DNA-repair vulnerability in HRR-mutated tumors.

Show evidence (1 reference)

DOI:10.1200/jco.23.02182 SUPPORT Human Clinical

"The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC)."

The FDA approval of the talazoparib-enzalutamide combination supports enzalutamide's inhibition of persistent androgen-receptor signaling (alongside talazoparib's HRR-directed synthetic lethality).

MODULATES Homologous Recombination Deficiency — Talazoparib is directed at the homologous-recombination-deficient state itself: PARP inhibition is synthetically lethal in tumors that cannot repair double-strand breaks by homologous recombination, which is why eligibility is written around HRR gene alteration.

Show evidence (1 reference)

DOI:10.1200/jco.23.02182 SUPPORT Human Clinical

"The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC)."

Approval restricted to HRR gene-mutated disease supports directing talazoparib at the homologous-recombination-deficient mechanism rather than at prostate cancer generally.

Show evidence (2 references)

DOI:10.1200/jco.23.02182 SUPPORT Human Clinical

"The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC)."

FDA approval summary supports talazoparib plus enzalutamide for HRR-mutated first-line mCRPC.

PMID:40315400 SUPPORT Other

"For patients with BRCA1/2 alterations who did not receive prior ARPI, the combination of PARPi and ARPI (talazoparib + enzalutamide, olaparib and/or niraparib + abiraterone) has shown clinical benefit."

The 2025 ASCO mCRPC guideline update supports the talazoparib-plus-enzalutamide PARPi/ARPI combination in BRCA1/2-altered disease.

Pembrolizumab for MSI-H or dMMR Disease

Action: immunotherapy Ontology label: Immunotherapy NCIT:C15262

Agent: pembrolizumab NCIT:C106432

Anti-PD-1 checkpoint blockade is a biomarker-selected option for metastatic prostate cancers with MSI-H/dMMR biology, where responses are enriched relative to TMB-high microsatellite-stable tumors.

Mechanism Target:

INHIBITS Immune-Suppressive Tumor Microenvironment — PD-1 blockade counteracts checkpoint-mediated immune evasion in biomarker-selected tumors with high neoantigen or mismatch-repair burden.

Show evidence (1 reference)

DOI:10.1158/1078-0432.ccr-23-3403 SUPPORT Human Clinical

"Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab."

Supports biomarker-selected PD-1 blockade (pembrolizumab) as the therapy directed at the immune-evasion mechanism in MSI-H/dMMR metastatic prostate cancer.

MODULATES Mismatch Repair Deficiency and Microsatellite Instability — Mismatch-repair deficiency is the selection criterion rather than the drug target: checkpoint blockade is offered because the hypermutated, microsatellite-unstable genome this mechanism produces raises neoantigen load.

Show evidence (1 reference)

DOI:10.1158/1078-0432.ccr-23-3403 SUPPORT Human Clinical

"Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab."

Candidacy defined by MSI-H/dMMR status supports linking pembrolizumab to the mismatch-repair-deficiency mechanism that generates it.

Show evidence (1 reference)

DOI:10.1158/1078-0432.ccr-23-3403 SUPPORT Human Clinical

"Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab."

This supports biomarker-selected pembrolizumab use in immunotherapy-responsive metastatic prostate cancer subsets.

🔬

Biochemical Markers

2

Prostate-Specific Antigen (PSA)

Show evidence (1 reference)

PMID:40063046 SUPPORT

"Recent guidelines encourage shared decision-making for prostate-specific antigen (PSA) screening."

This supports PSA as the key biomarker around which screening and early detection decisions are organized.

Plasma testosterone

Context: Pharmacodynamic marker of androgen deprivation in advanced prostate cancer; suppression toward castrate levels indicates reduced androgen ligand drive.

Pathograph Readouts

Pharmacodynamic Marker Of Androgen Receptor Signaling Dependence Positive Regulatory Surrogate

Higher plasma testosterone indicates greater androgen ligand availability for AR signaling, whereas effective GnRH-antagonist therapy suppresses testosterone as the pharmacodynamic endpoint.

FDA-SE-adult-cancer-015 FDA

Plasma testosterone levels

Traditional Validated Surrogate Endpoint

Patients with advanced prostate cancer

Show evidence (2 references)

PMID:40063046 SUPPORT Human Clinical

"Treatment of metastatic prostate cancer primarily relies on androgen deprivation therapy, most commonly through medical castration with gonadotropin-releasing hormone agonists."

This review supports testosterone suppression through medical castration as a central pharmacodynamic mechanism in metastatic prostate cancer.

PMID:34771580 SUPPORT Human Clinical

"Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR)."

This review supports the linked AR-signaling pathograph node that plasma testosterone pharmacodynamically reports on.

🪜

Stages

2

Localized

Organ-confined or locoregional adenocarcinoma, frequently indolent enough for risk-adapted surveillance, and curable with radical prostatectomy or radiotherapy.

Metastatic

Advanced prostate adenocarcinoma that has spread beyond the prostate and regional lymph nodes, most commonly to bone, lymph node, liver, and lung. The metastatic state is sustained by persistent androgen receptor signaling, lineage plasticity under treatment pressure, osteoblastic bone tropism, and progressive emergence of castration resistance.

Folded in from the former Metastatic_Prostate_Cancer entry (cancer granularity ladder, design decisions §3a). Bone metastasis is the defining metastatic phenotype, but liver and lung involvement become more common in late castration-resistant disease; the central biologic transition is continued AR dependence followed by adaptive AR-independent escape. The Osteoblastic Bone Tropism and Clonal Evolution and Lineage Plasticity pathophysiology nodes carry the stage-specific mechanism content.

Show evidence (1 reference)

PMID:40063046 SUPPORT Human Clinical

"Approximately 10% of patients present with metastatic prostate cancer, which has a 5-year survival rate of 37%."

Quantifies presentation frequency and survival for the metastatic stage.

📊

Prevalence

2

Prostate cancers

99

Adenocarcinoma accounts for virtually all prostate cancer histologies.

Show evidence (1 reference)

PMID:40063046 SUPPORT

"The most common type of prostate cancer is adenocarcinoma (≥99%), and the median age at diagnosis is 67 years."

This abstract explicitly states that adenocarcinoma comprises at least 99% of prostate cancers.

Newly diagnosed prostate cancer

75

Most patients present with disease still localized to the prostate.

Show evidence (1 reference)

PMID:40063046 SUPPORT

"At diagnosis, approximately 75% of patients have cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%."

This provides the stage distribution at presentation for prostate cancer, which is overwhelmingly adenocarcinoma.

📊

Related Datasets

3

Plasma-Seq of patients with metastatic prostate cancer ega:EGAS00001000451

Study 1 In this study we analysed patients with metastatic prostate cancer to scan their tumor genomes noninvasively in plasma DNA. We wanted to make whole-genome analysis from plasma DNA amenable to clinical routine applications and developed an approach based on a benchtop high-throughput platform, i.e. Illuminas MiSeq instrument. We performed whole-genome sequencing from plasma at a shallow sequencing depth to establish a genome-wide copy number profile of the tumor at low costs within 2 days. The genome-wide profiling in the plasma of our patients revealed multiple copy number aberrations including those previously reported in prostate tumors, such as losses in 8p and gains in 8q.

human

PMID:23561577

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Metastatic Prostate Cancer"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Identification of mutations and structural rearrangements in plasma DNA form metastatic prostate cancer patients ega:EGAS00001000453

In this study we analysed patients with metastatic prostate cancer to scan their tumor genomes noninvasively in plasma DNA. We enriched 1.3 Mbp of seven plasma DNAs (4 CRPC cases: CRPC1-3 and CRPC5; 3 CSPC cases: CSPC1-2 and CSPC4) including exonic sequences of 55 cancer genes and 38 introns of 18 genes, where fusion breakpoints have been described using Sure Select Custom DNA Kit.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Metastatic Prostate Cancer"); description-level mentions were not accepted. EGA study_type: Resequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer ega:EGAS00001001018

Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyze 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP, SHQ1), and driver amplifications (AR, MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases.

human

European Genome-phenome Archive study, matched because the disease is named in the study's own title ("Metastatic Prostate Cancer"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.

{ }

Source YAML

click to show

name: Prostate Adenocarcinoma
creation_date: '2026-04-12T05:10:57Z'
description: >-
  Prostate adenocarcinoma is the predominant histologic form of prostate cancer,
  arising from prostatic glandular epithelium and maintained by androgen
  receptor-centered transcriptional programs. Its biology spans indolent
  localized tumors, molecularly defined aggressive subtypes with PTEN loss or
  TMPRSS2:ERG fusion, and advanced states marked by metastatic dissemination,
  signaling bypass, and relative immune quiescence.
categories:
- Genitourinary Cancer
- Adenocarcinoma
- Solid Tumor
parents:
- prostate cancer
disease_term:
  preferred_term: prostate adenocarcinoma
  term:
    id: MONDO:0005082
    label: prostate adenocarcinoma
prevalence:
- population: Prostate cancers
  percentage: 99
  notes: Adenocarcinoma accounts for virtually all prostate cancer histologies.
  evidence:
  - reference: PMID:40063046
    reference_title: "Prostate Cancer: A Review."
    supports: SUPPORT
    snippet: "The most common type of prostate cancer is adenocarcinoma (≥99%), and the median age at diagnosis is 67 years."
    explanation: This abstract explicitly states that adenocarcinoma comprises at least 99% of prostate cancers.
- population: Newly diagnosed prostate cancer
  percentage: 75
  notes: Most patients present with disease still localized to the prostate.
  evidence:
  - reference: PMID:40063046
    reference_title: "Prostate Cancer: A Review."
    supports: SUPPORT
    snippet: "At diagnosis, approximately 75% of patients have cancer localized to the prostate, which is associated with a 5-year survival rate of nearly 100%."
    explanation: This provides the stage distribution at presentation for prostate cancer, which is overwhelmingly adenocarcinoma.
stages:
- name: Localized
  description: >-
    Organ-confined or locoregional adenocarcinoma, frequently indolent enough
    for risk-adapted surveillance, and curable with radical prostatectomy or
    radiotherapy.
- name: Metastatic
  description: >-
    Advanced prostate adenocarcinoma that has spread beyond the prostate and
    regional lymph nodes, most commonly to bone, lymph node, liver, and lung.
    The metastatic state is sustained by persistent androgen receptor
    signaling, lineage plasticity under treatment pressure, osteoblastic bone
    tropism, and progressive emergence of castration resistance.
  notes: >-
    Folded in from the former Metastatic_Prostate_Cancer entry (cancer
    granularity ladder, design decisions §3a). Bone metastasis is the defining
    metastatic phenotype, but liver and lung involvement become more common in
    late castration-resistant disease; the central biologic transition is
    continued AR dependence followed by adaptive AR-independent escape. The
    Osteoblastic Bone Tropism and Clonal Evolution and Lineage Plasticity
    pathophysiology nodes carry the stage-specific mechanism content.
  evidence:
  - reference: PMID:40063046
    reference_title: "Prostate Cancer: A Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Approximately 10% of patients present with metastatic prostate cancer, which has a 5-year survival rate of 37%.
    explanation: Quantifies presentation frequency and survival for the metastatic stage.
pathophysiology:
- name: Androgen Receptor Signaling Dependence
  description: >-
    Prostate adenocarcinoma is organized around androgen receptor (AR) signaling,
    which sustains lineage identity, proliferation, and survival and therefore
    remains the dominant therapeutic dependency across much of the disease course.
  evidence:
  - reference: PMID:34771580
    reference_title: 'Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies.'
    supports: SUPPORT
    snippet: "Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR)."
    explanation: The abstract identifies AR as the central mechanistic axis that has driven therapy development in prostate cancer.
  cell_types:
  - preferred_term: epithelial cell of prostate
    term:
      id: CL:0002231
      label: epithelial cell of prostate
  biological_processes:
  - preferred_term: androgen receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0030521
      label: androgen receptor signaling pathway
  locations:
  - preferred_term: prostate gland
    term:
      id: UBERON:0002367
      label: prostate gland
  downstream:
  - target: Lipogenic Metabolic Reprogramming
    description: AR activation promotes anabolic lipid metabolism that supports tumor growth.
  - target: Signaling Bypass and Castration Resistance
    description: Treatment pressure selects AR-reactivated and AR-bypass states.
  - target: TMPRSS2:ERG Fusion-Driven ETS Activation
    description: >-
      Androgen-responsive TMPRSS2 promoter elements drive aberrant ERG
      overexpression in the roughly half of tumors carrying the fusion.
  - target: AR-Mediated Mutagenesis at Androgen Receptor Binding Sites
    description: >-
      Sustained AR occupancy is itself mutagenic, raising the local mutation rate
      and concentrating chained rearrangements at tumor-specific AR binding sites.
- name: TMPRSS2:ERG Fusion-Driven ETS Activation
  genetic_context:
    variant_origin: SOMATIC
  description: >-
    In approximately half of prostate adenocarcinomas an androgen-responsive
    TMPRSS2 promoter is fused to the ETS transcription factor ERG, placing ERG
    under androgen control and driving its aberrant overexpression. The
    resulting ETS transcriptional program promotes an invasion-associated,
    less-differentiated phenotype and defines the predominant molecular subtype
    of the disease.
  evidence:
  - reference: PMID:16254181
    reference_title: 'Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we demonstrated that 23 of 29 prostate cancer samples harbor rearrangements in ERG or ETV1"
    explanation: Fluorescence in situ hybridization in human prostate cancer tissue established recurrent ERG/ETV1 rearrangements as a frequent somatic event.
  - reference: PMID:16254181
    reference_title: 'Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Cell line experiments suggest that the androgen-responsive promoter elements of TMPRSS2 mediate the overexpression of ETS family members in prostate cancer."
    explanation: This identifies the androgen-driven TMPRSS2 promoter as the mechanism placing ETS factors such as ERG under aberrant transcriptional control.
  - reference: PMID:18283340
    reference_title: 'Role of the TMPRSS2-ERG gene fusion in prostate cancer.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Introduction of the ERG gene fusion product into primary or immortalized benign prostate epithelial cells induced an invasion-associated transcriptional program but did not increase cellular proliferation or anchorage-independent growth."
    explanation: Functional introduction of the ERG fusion product activates an invasion-associated transcriptional program, indicating the fusion contributes to invasion rather than proliferation.
  cell_types:
  - preferred_term: epithelial cell of prostate
    term:
      id: CL:0002231
      label: epithelial cell of prostate
  biological_processes:
  - preferred_term: ETS (ERG) target gene transcriptional activation
    modifier: INCREASED
    term:
      id: GO:0045944
      label: positive regulation of transcription by RNA polymerase II
  locations:
  - preferred_term: prostate gland
    term:
      id: UBERON:0002367
      label: prostate gland
  downstream:
  - target: Epithelial-Mesenchymal Transition
    description: >-
      ERG-driven invasion-associated transcriptional reprogramming promotes the
      invasive cellular phenotype that precedes distant spread.
- name: Lipogenic Metabolic Reprogramming
  description: >-
    Prostate adenocarcinoma shows unusually strong dependence on de novo fatty
    acid synthesis, an AR-linked metabolic program that supports membrane
    biogenesis, signaling, and aggressive tumor behavior.
  evidence:
  - reference: PMID:34145040
    reference_title: 'Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?'
    supports: SUPPORT
    snippet: "Prostate cancer exhibits unique metabolism with high rates of de novo fatty acid synthesis driven by activation of the androgen receptor (AR)."
    explanation: This directly supports AR-driven lipogenic reprogramming as a core metabolic feature of prostate cancer.
  biological_processes:
  - preferred_term: fatty acid biosynthetic process
    modifier: INCREASED
    term:
      id: GO:0006633
      label: fatty acid biosynthetic process
- name: Signaling Bypass and Castration Resistance
  conforms_to: "mtor_androgen_deprivation_resistance#mTORC1 Hyperactivation"
  description: >-
    As disease progresses under androgen deprivation, resistant clones emerge
    through AR splice variants, AR overexpression or mutation, and activation of
    PI3K/AKT and other compensatory pathways that restore growth despite ARSI therapy.
    This node conforms to the mtor_androgen_deprivation_resistance module: AR-pathway
    blockade relieves feedback inhibition of the PI3K/AKT axis (potentiated by PTEN
    loss in this disease), driving compensatory mTORC1 hyperactivation that sustains
    survival under androgen blockade — the biological basis for the co-targeting
    (mTOR-inhibitor plus ARPI) therapeutic rationale.
  evidence:
  - reference: PMID:34771580
    reference_title: 'Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies.'
    supports: SUPPORT
    snippet: "DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins."
    explanation: This abstract sentence directly describes the bypass pathways that support AR-independent or incompletely AR-dependent progression.
  - reference: PMID:21575859
    reference_title: "Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Similarly, AR inhibition activates AKT signaling by reducing levels of
      the AKT phosphatase PHLPP. Thus, these two oncogenic pathways
      cross-regulate each other by reciprocal feedback. Inhibition of one
      activates the other, thereby maintaining tumor cell survival.
    explanation: >-
      Demonstrates the reciprocal AR-PI3K/AKT feedback in prostate cancer models
      that converts AR blockade into compensatory PI3K/AKT (and downstream mTORC1)
      activation; folded in from the former Metastatic_Prostate_Cancer entry.
  - reference: PMID:30535926
    reference_title: "Enzalutamide: A Review in Castration-Resistant Prostate Cancer."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Oral enzalutamide (Xtandi®), a second generation androgen receptor inhibitor, is indicated for the treatment of castration-resistant prostate cancer (CRPC) in numerous countries worldwide, with specific indications in this patient population varying between individual countries.
    explanation: Supports the continued centrality of AR signaling in metastatic castration-resistant disease.
  biological_processes:
  - preferred_term: phosphatidylinositol 3-kinase/protein kinase B signal transduction
    modifier: INCREASED
    term:
      id: GO:0043491
      label: phosphatidylinositol 3-kinase/protein kinase B signal transduction
  - preferred_term: TORC1 Signaling
    modifier: INCREASED
    term:
      id: GO:0038202
      label: TORC1 signaling
  downstream:
  - target: Epithelial-Mesenchymal Transition
    description: Resistant signaling states promote invasive cellular reprogramming that precedes distant spread.
  - target: Clonal Evolution and Lineage Plasticity
    description: Treatment pressure selects resistant subclones and alternative cell states.
- name: Epithelial-Mesenchymal Transition
  conforms_to: "invasion_and_metastasis#Epithelial-Mesenchymal Transition Activation"
  description: >-
    Progression from organ-confined adenocarcinoma toward invasive disease
    involves signaling networks that promote epithelial-to-mesenchymal
    transition and increased migratory capacity.
  evidence:
  - reference: PMID:40372974
    reference_title: 'Signalling pathways in a nutshell: from pathogenesis to therapeutical implications in prostate cancer.'
    supports: SUPPORT
    snippet: "Particular pathways that allow cells to proliferate by creating a network of new blood vessels have been documented, whereas other pathways are primarily involved with a migration to distant body parts, partially through the process of epithelial-mesenchymal transition (EMT)."
    explanation: This review abstract explicitly links prostate cancer progression and distant spread to EMT-related signaling pathways.
  biological_processes:
  - preferred_term: epithelial to mesenchymal transition
    modifier: INCREASED
    term:
      id: GO:0001837
      label: epithelial to mesenchymal transition
  downstream:
  - target: Metastatic Dissemination
    description: EMT-like reprogramming supports invasion and subsequent distant spread.
- name: Metastatic Dissemination
  description: >-
    Advanced prostate adenocarcinoma can disseminate beyond the prostate to
    distant metastatic sites as disease progresses or recurs after definitive
    local therapy.
  downstream:
  - target: Osteoblastic Bone Tropism
    description: >-
      Disseminated prostate cancer cells preferentially colonize bone, where
      tumor-stromal signaling produces the characteristic osteoblastic lesions.
  evidence:
  - reference: PMID:40063046
    reference_title: "Prostate Cancer: A Review."
    supports: SUPPORT
    snippet: "Despite definitive therapy, 2% to 56% of men with localized disease develop distant metastases, depending on tumor risk factors."
    explanation: This directly supports progression from initially localized prostate cancer to distant metastatic dissemination.
- name: Immune-Suppressive Tumor Microenvironment
  description: >-
    Prostate adenocarcinoma typically has a relatively immunologically cold
    microenvironment with weak endogenous antitumor activity, contributing to the
    limited single-agent activity of checkpoint immunotherapy in unselected disease.
  evidence:
  - reference: PMID:33106940
    reference_title: 'Immunotherapy in prostate cancer: new horizon of hurdles and hopes.'
    supports: SUPPORT
    snippet: "Tumor progression and patient outcomes depend on complex cellular and molecular interactions of the tumor with the host immune system, driven rather dormant in case of PCa."
    explanation: This supports the relatively dormant immune contexture of prostate cancer and the importance of tumor-immune interactions.
  biological_processes:
  - preferred_term: negative regulation of immune response
    modifier: INCREASED
    term:
      id: GO:0050777
      label: negative regulation of immune response
- name: Osteoblastic Bone Tropism
  description: >-
    Bone is the dominant metastatic niche in prostate cancer. Tumor-stromal signaling
    stimulates abnormal woven bone formation and couples osteoblastic and osteolytic
    remodeling, producing fragile but radiographically dense skeletal lesions.
  evidence:
  - reference: PMID:18639279
    reference_title: "Histopathological assessment of prostate cancer bone osteoblastic metastases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: In contrast with metastases caused by other carcinomas such as breast, thyroid, kidney, and lung that destroy bone and are termed “osteolytic,” prostate cancer generally causes a bone-forming or “osteoblastic” response.
    explanation: This directly supports the osteoblastic bone tropism that distinguishes metastatic prostate cancer.
  biological_processes:
  - preferred_term: positive regulation of ossification
    modifier: INCREASED
    term:
      id: GO:0045778
      label: positive regulation of ossification
- name: Clonal Evolution and Lineage Plasticity
  description: >-
    Under treatment pressure, metastatic prostate cancer accumulates resistant subclones
    and can adopt alternative lineage states that support persistence after AR-targeted
    therapy.
  biological_processes:
  - preferred_term: cell fate commitment
    modifier: ABNORMAL
    term:
      id: GO:0045165
      label: cell fate commitment
- name: AR-Mediated Mutagenesis at Androgen Receptor Binding Sites
  biological_scale: MOLECULAR
  description: >-
    Androgen receptor binding is a mutagenic event and not only a transcriptional
    one. Whole-genome analysis of the Pan Prostate Cancer Group cohort identifies
    AR-mediated mutagenesis as the most recurrent integrated mutational footprint
    in chromosomally unstable primary tumors, raising the local mutation rate at
    tumor-specific AR binding sites (TARBSs) and concentrating chromoplexy - chains
    of interchromosomal complex rearrangements - specifically and uniquely at those
    sites. Chromoplexy is an established generator of ERG fusions, and it is
    concentrated at AR binding sites, so this process is the most likely origin of
    the androgen-driven fusion events this entry already models - but the step that
    AR binding is what localizes the chromoplexy remains an inference from
    co-localization, not a demonstrated one. Its intensity tracks
    the epigenetic state of the site rather than AR occupancy alone: TARBSs are
    enriched for unmethylated CpGs, which places the process in early-replicating,
    transcriptionally active chromatin and accounts for the local depletion of the
    5-methylcytosine-deamination signature SBS1 there.
  evidence:
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMFs were strongly influenced by regional biases in the genome, most prevalently androgen receptor-mediated mutagenesis and replication stress."
    explanation: >-
      Identifies AR-mediated mutagenesis as one of the two dominant regional
      influences shaping mutational processes across primary prostate cancer
      genomes, which is the claim this node makes.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found chromoplexy events to be specifically and uniquely enriched at tumour-specific ARBSs"
    explanation: >-
      Establishes the structural-variant class this node attributes to AR binding,
      and that the enrichment is specific to tumor-specific binding sites rather
      than to AR binding in general.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This suggests that the AR mutagenicity at enhancers and promoters is conditioned on existing CpG methylation levels."
    explanation: >-
      Supports the conditioning of AR mutagenicity on the local methylation state,
      which is why this node treats the epigenetic context as part of the mechanism
      rather than as background.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which showed an enrichment of unmethylated CpGs at TARBS compared to NARBS"
    explanation: >-
      Long-read sequencing of tumors in the same cohort provides the direct
      methylation measurement behind the hypomethylated-TARBS statement in this
      node's description.
  cell_types:
  - preferred_term: epithelial cell of prostate
    term:
      id: CL:0002231
      label: epithelial cell of prostate
  biological_processes:
  - preferred_term: androgen receptor signaling pathway
    modifier: INCREASED
    term:
      id: GO:0030521
      label: androgen receptor signaling pathway
  - preferred_term: chromoplexy (chained interchromosomal rearrangement) at AR binding sites
    modifier: INCREASED
    term:
      id: GO:0006310
      label: DNA recombination
  locations:
  - preferred_term: prostate gland
    term:
      id: UBERON:0002367
      label: prostate gland
  downstream:
  - target: TMPRSS2:ERG Fusion-Driven ETS Activation
    description: >-
      Chromoplexy generates ERG fusions and precedes them in the clonal ordering,
      and chromoplexy is specifically enriched at tumor-specific AR binding sites.
      The edge therefore runs generation-then-expression: this node makes the
      rearrangement, the AR-dependency node transcribes through it.
    evidence:
    - reference: PMID:23622249
      reference_title: Punctuated evolution of prostate cancer genomes.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Chromoplexy is active prior to ETS gene fusions, however, and generated ERG fusions in many instances."
      explanation: >-
        Whole-genome clonal ordering in prostate tumors places chromoplexy before
        the ETS fusion and attributes ERG fusion formation to it, which is the
        generative step this edge asserts.
    - reference: PMID:42717097
      reference_title: Integrated signatures define mutational processes in prostate cancer.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We found chromoplexy events to be specifically and uniquely enriched at tumour-specific ARBSs"
      explanation: >-
        Locates that generative process at AR binding sites, which is what connects
        it to this node rather than to chromoplexy in general.
  - target: Clonal Evolution and Lineage Plasticity
    description: >-
      Recurrent AR-directed rearrangement adds heritable structural diversity for
      selection to act on.
  - target: Metastatic Dissemination
    description: >-
      Tumors dominated by AR-mediated mutagenesis reached metastasis sooner than
      chromosomally stable tumors in the PPCG cohort.
  notes: >-
    Deliberately carries no genetic_context block. The lesion here is a
    process-level bias in where mutations land, not a single somatic variant, and
    a SOMATIC variant_origin on this node would be read by the cancer-cell-of-origin
    derivation as a second transforming lesion alongside the ETS fusion node.


    Two limits on the edge into the ETS-fusion node, both of which the sources
    state themselves. First, the AR attribution is inferential: the PPCG cohort
    shows chromoplexy enriched at AR binding sites, and the chromoplexy paper says
    of the same link that "this hypothesis awaits experimental validation". The
    experimental arm - androgen-induced double-strand breaks at translocation
    partners - exists in the earlier TOP2B and AID literature, which this entry
    does not yet cite; citing it is the obvious next step. Second, the association
    the PPCG paper reports between this footprint and ETS-fusion status (Cohen's
    d = 0.75) is directionally ambiguous on its own, since a fusion raises
    AR-pathway output. The direction of this edge rests on the clonal ordering in
    PMID:23622249, not on that correlation.

- name: Replication Stress-Driven Chromosomal Instability
  biological_scale: CELLULAR
  conforms_to: "genome_instability_mutation#Genome-Maintenance Defect or Replication Stress"
  description: >-
    Dysfunctional DNA replication is the dominant mutational process in roughly a
    quarter of chromosomally unstable primary prostate cancers, resolving into two
    integrated footprints: one combining mitotic-machinery defects with replication
    stress, and one linked to SPOP and WNT-pathway alterations. Faulty replicated
    DNA persisting into mitosis yields copy-number and complex structural change
    rather than a distinctive base-substitution spectrum, which is why the process
    was only resolved by integrating substitution, indel, copy-number and complex
    structural-variant signatures. Clinically this footprint separates from the
    metastasis-associated processes in two ways: it predominates in late-onset
    disease, and higher activity of the SPOP-associated footprint marked tumors
    that failed later on AR pathway inhibitors than on taxanes.
  evidence:
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study also identified a pervasive role for replication stress in prostate cancer, with dysfunctional DNA replication as the dominant mutational process in 28% of prostate cancers with CIN"
    explanation: >-
      Quantifies the share of chromosomally unstable primary tumors in which
      replication stress is the dominant mutational process, the central claim of
      this node.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting faulty replicated DNA after replication stress that persists into mitotic defects"
    explanation: >-
      States the mechanistic link this node models between replication stress and
      the mitotic-defect footprint, rather than treating the two as separate
      processes.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMF6 exhibited increased activity in cases with mutations in SPOP and WNT-pathway genes APC and SOX17"
    explanation: >-
      Provides the driver-gene association behind the SPOP-linked replication-stress
      footprint named in this node's description.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMF6 (replication stress) was predominant in late-onset tumours, whereas IMF8 (HRD) was enriched in early-onset cases"
    explanation: >-
      Supports the age-at-diagnosis split this node records, and the contrast with
      the homologous-recombination-deficient footprint curated separately below.
  cell_types:
  - preferred_term: epithelial cell of prostate
    term:
      id: CL:0002231
      label: epithelial cell of prostate
  biological_processes:
  - preferred_term: DNA replication under replication stress
    modifier: ABNORMAL
    term:
      id: GO:0006260
      label: DNA replication
  - preferred_term: chromosome organization
    modifier: ABNORMAL
    term:
      id: GO:0051276
      label: chromosome organization
  downstream:
  - target: Clonal Evolution and Lineage Plasticity
    description: >-
      Copy-number and structural change generated by unresolved replication stress
      expands the subclonal repertoire available to treatment selection.

- name: Reactive Oxygen Species-Driven Mutagenesis
  biological_scale: MOLECULAR
  description: >-
    A distinct integrated footprint attributes part of the mutation burden to
    oxidative DNA damage handled by a faulty base-excision repair pathway, marked by
    the substitution signature SBS18 and concentrated in late-replicating regions.
    It is anti-correlated with tumor hypoxia score, so it reads as an oxygen-dependent
    damage process rather than as a consequence of the hypoxic niche. Among the
    footprints that carry prognostic weight, this is one of the four associated with
    shorter time to metastasis, which makes oxidative mutagenesis a candidate risk
    axis independent of Gleason grade group and tumor mutational burden.
  evidence:
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMF2 (ROS mutagenesis) was significantly associated with SBS18"
    explanation: >-
      Ties the footprint this node curates to its defining base-substitution
      signature.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a signature linked with faulty BER and DNA damage induced by ROS"
    explanation: >-
      Gives the aetiology assigned to that signature - reactive-oxygen-species
      damage repaired through a defective base-excision pathway - which is the
      mechanism this node models.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Four IMFs, present in 37% of primary tumours, were significantly associated with shorter time to metastasis."
    explanation: >-
      Establishes that a defined subset of these mutational processes, this one
      among them, carries prognostic weight for metastasis in primary disease.
  cell_types:
  - preferred_term: epithelial cell of prostate
    term:
      id: CL:0002231
      label: epithelial cell of prostate
  biological_processes:
  - preferred_term: response to oxidative stress
    modifier: INCREASED
    term:
      id: GO:0006979
      label: response to oxidative stress
  - preferred_term: base-excision repair
    modifier: DECREASED
    term:
      id: GO:0006284
      label: base-excision repair
  downstream:
  - target: Metastatic Dissemination
    description: >-
      Tumors dominated by oxidative mutagenesis progressed to metastasis sooner than
      chromosomally stable tumors, independent of grade, stage and mutational burden.
  - target: Clonal Evolution and Lineage Plasticity
    description: >-
      Unrepaired oxidative lesions raise the substitution burden feeding subclonal
      diversification.

- name: Homologous Recombination Deficiency
  biological_scale: MOLECULAR
  conforms_to: "genome_instability_mutation#Genome-Maintenance Defect or Replication Stress"
  description: >-
    Canonical homologous-recombination deficiency is the therapeutically actionable
    caretaker defect in prostate cancer and the footprint most closely tied to BRCA2
    alteration, combining the substitution signature SBS3, the microhomology-mediated
    deletion signature ID6, and complex structural and copy-number signatures of
    impaired repair. It is uncommon in primary disease - fewer than 3% of primary
    tumors - but is enriched in early-onset cases and is one of the four footprints
    associated with shorter time to metastasis. This is the mechanism the entry's
    PARP-inhibitor combination treatment is directed at.
  evidence:
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMF8 (impaired HR) was correlated with mutational signatures SBS3, ID6, cSV6 and CX3 related to impaired HR"
    explanation: >-
      Names the multi-modality signature combination that defines this footprint,
      which is the basis for treating it as a single mechanism rather than as
      several independent signatures.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMF8 activity was also significantly higher in cases with BRCA2 mutations"
    explanation: >-
      Supplies the driver-gene association that assigns a canonical
      homologous-recombination aetiology to this footprint.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "fewer than 3% of primary prostate cancers exhibit a deficiency in this repair mechanism"
    explanation: >-
      Quantifies how rare canonical homologous-recombination deficiency is in
      primary disease, which is the reason this node is curated alongside, rather
      than in place of, the other mutational processes.
  cell_types:
  - preferred_term: epithelial cell of prostate
    term:
      id: CL:0002231
      label: epithelial cell of prostate
  biological_processes:
  - preferred_term: double-strand break repair via homologous recombination
    modifier: DECREASED
    term:
      id: GO:0000724
      label: double-strand break repair via homologous recombination
  downstream:
  - target: Metastatic Dissemination
    description: >-
      Homologous-recombination-deficient primary tumors carried a high risk of
      progression to metastasis relative to chromosomally stable tumors.
  - target: Clonal Evolution and Lineage Plasticity
    description: >-
      Loss of accurate double-strand break repair drives the structural
      diversification on which subclonal selection acts.

- name: CDK12-Associated Non-Canonical Homologous Recombination Impairment
  biological_scale: MOLECULAR
  conforms_to: "genome_instability_mutation#Genome-Maintenance Defect or Replication Stress"
  description: >-
    A second impaired-homologous-recombination footprint is separable from the
    canonical BRCA-driven one by both its driver and its damage pattern. It is
    associated with CDK12 mutation, which phenocopies impaired homologous
    recombination without BRCA1/2 loss, and its structural signature is dominated by
    tandem duplications rather than by microhomology-mediated deletion. It is
    enriched in patients of African ancestry and confers a high risk of progression
    to metastasis. Curating it separately matters clinically, because a tumor can
    carry a homologous-recombination-like footprint while being negative for the
    BRCA alterations that current PARP-inhibitor eligibility is written around.
  evidence:
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMF5 (non-canonical impaired HR) had significantly higher activity in tumours with mutations in CDK12"
    explanation: >-
      Provides the driver association that separates this footprint from the
      canonical BRCA2-associated one curated above.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "which has been shown to phenocopy impaired HR in the absence of mutations in BRCA1/2"
    explanation: >-
      States the mechanistic basis for calling this a homologous-recombination
      impairment despite intact BRCA1/2, which is what makes it non-canonical.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMF5 activities were significantly correlated with cSV4, characterized by tandem duplications"
    explanation: >-
      Gives the distinctive structural-variant pattern - a tandem-duplicator
      phenotype - that distinguishes this footprint from canonical
      homologous-recombination deficiency.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Notably, this mutational process was enriched in patients of African ancestry"
    explanation: >-
      Records the ancestry enrichment reported for this footprint, which bears on
      who is missed by BRCA-centric eligibility criteria.
  cell_types:
  - preferred_term: epithelial cell of prostate
    term:
      id: CL:0002231
      label: epithelial cell of prostate
  biological_processes:
  - preferred_term: double-strand break repair via homologous recombination
    modifier: DECREASED
    term:
      id: GO:0000724
      label: double-strand break repair via homologous recombination
  - preferred_term: tandem duplication formation
    modifier: INCREASED
    term:
      id: GO:0006310
      label: DNA recombination
  downstream:
  - target: Metastatic Dissemination
    description: >-
      Tumors dominated by this footprint showed the highest hazard of progression to
      metastasis among the dominant mutational processes assessed.
  - target: Clonal Evolution and Lineage Plasticity
    description: >-
      A tandem-duplicator genome generates recurrent copy gain across many loci,
      broadening the substrate for selection.

- name: Mismatch Repair Deficiency and Microsatellite Instability
  biological_scale: MOLECULAR
  conforms_to: "genome_instability_mutation#Genome-Maintenance Defect or Replication Stress"
  description: >-
    Loss of DNA mismatch repair, most often through MSH2 alteration, produces the
    replicative-slippage footprint that combines the MMR-associated substitution
    signatures with the characteristic indel signature, and yields microsatellite
    instability. Its topographical behaviour is diagnostic: where the other
    mutational processes are strongly biased by replication timing and chromatin
    state, mismatch-repair-deficient tumors mutate at a near-uniform rate across the
    genome, consistent with replication-coupled repair normally being most efficient
    in early-replicating regions. Unlike the other footprints curated here it is also
    detectable in chromosomally stable tumors. This is the mechanism behind the
    entry's biomarker-selected checkpoint-blockade indication.
  evidence:
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMF1 (MMRd) activity correlated with MMRd-related mutational signatures SBS15, SBS21 and ID2"
    explanation: >-
      Ties this footprint to the mismatch-repair signature set that defines it.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMF1 had higher activity in cases with microsatellite instability"
    explanation: >-
      Connects the footprint to the microsatellite-instability phenotype that this
      node names and that the entry's checkpoint-blockade indication is written
      around.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tumours with high IMF1 exhibited a near-uniform mutation rate across the genome"
    explanation: >-
      Supports the distinguishing topographical property recorded in this node's
      description - absence of the regional bias seen in the other footprints.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we also found signatures of MMRd in chromosomally stable tumours"
    explanation: >-
      Supports the statement that this process is not confined to chromosomally
      unstable disease, unlike the other footprints curated in this section.
  cell_types:
  - preferred_term: epithelial cell of prostate
    term:
      id: CL:0002231
      label: epithelial cell of prostate
  biological_processes:
  - preferred_term: mismatch repair
    modifier: DECREASED
    term:
      id: GO:0006298
      label: mismatch repair
  downstream:
  - target: Immune-Suppressive Tumor Microenvironment
    description: >-
      The hypermutated, microsatellite-unstable genome raises neoantigen load, which
      is the basis for biomarker-selected checkpoint blockade in this subset.
  - target: Clonal Evolution and Lineage Plasticity
    description: >-
      An elevated, uniformly distributed substitution and indel rate accelerates
      subclonal diversification.

- name: APOBEC Cytidine Deaminase Mutagenesis
  biological_scale: MOLECULAR
  description: >-
    APOBEC-family cytidine deaminase activity contributes a separate footprint
    carrying the APOBEC substitution signatures. Its regional behaviour links it to
    structural catastrophe rather than to replication timing: APOBEC-signature
    mutations cluster around complex structural-variant breakpoints, consistent with
    single-stranded DNA exposed during chromothripsis being edited by the deaminase.
    Clonality analysis places APOBEC mutations early in tumor evolution while the
    impaired-recombination signatures accompanying this footprint appear subclonally,
    which is the argument for reading APOBEC editing as the driving aetiology here
    and the recombination signatures as a later, separate process.
  evidence:
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IMF7 (APOBEC mutagenesis) was correlated with APOBEC-associated signatures SBS2 and SBS13"
    explanation: >-
      Ties this footprint to the cytidine-deaminase substitution signatures that
      define it.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "suggesting APOBEC-mediated editing at chromothriptic breakpoints"
    explanation: >-
      Supports the spatial coupling between APOBEC editing and complex
      structural-variant breakpoints that this node models.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We found that APOBEC-related mutations often occurred clonally, while impaired HR mutations appeared subclonally"
    explanation: >-
      Provides the timing argument for assigning APOBEC activity, rather than
      impaired recombination, as this footprint's aetiology.
  cell_types:
  - preferred_term: epithelial cell of prostate
    term:
      id: CL:0002231
      label: epithelial cell of prostate
  molecular_functions:
  - preferred_term: APOBEC3 cytidine deaminase activity on single-stranded DNA
    modifier: INCREASED
    term:
      id: GO:0004126
      label: cytidine deaminase activity
  downstream:
  - target: Clonal Evolution and Lineage Plasticity
    description: >-
      Clonal APOBEC editing establishes an early substitution burden on which later
      selection operates.

histopathology:
- name: Acinar Adenocarcinoma
  finding_term:
    preferred_term: Prostate Acinar Adenocarcinoma
    term:
      id: NCIT:C5596
      label: Prostate Acinar Adenocarcinoma
  description: >-
    Classic acinar adenocarcinoma is the dominant morphologic pattern in prostate
    adenocarcinoma and the reference point against which less common glandular and
    non-glandular variants are compared.
  evidence:
  - reference: PMID:36081403
    reference_title: 'Histological patterns, subtypes and aspects of prostate cancer: different aspects, different outcomes.'
    supports: SUPPORT
    snippet: "The most common prostatic cancers (PCa) are acinary adenocarcinomas."
    explanation: This directly supports acinar adenocarcinoma as the dominant histology among prostate cancers.
phenotypes:
- category: Genitourinary
  name: Lower Urinary Tract Symptoms
  phenotype_term:
    preferred_term: Lower Urinary Tract Symptoms
  description: >-
    Localized tumors can present with obstructive or irritative urinary symptoms
    including frequency, nocturia, hesitancy, and dysuria.
  notes: Composite LUTS phenotype spanning urinary frequency, nocturia, hesitancy, and dysuria; no single precise HPO term is assigned here.
  evidence:
  - reference: PMID:42074717
    reference_title: 'Prevalence of Benign Prostatic Hyperplasia and Prostate Cancer Among Men Presenting with Lower Urinary Tract Symptoms at a Tertiary Referral Hospital in Dar es Salaam, Tanzania: A Retrospective Cross-Sectional Study.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Lower urinary tract symptoms (LUTSs) are among the most common urological complaints in older men, frequently arising from benign prostatic hyperplasia (BPH) or prostate cancer (PCa)."
    explanation: This supports lower urinary tract symptoms as a common presenting complaint that can arise from prostate cancer.
- category: Genitourinary
  name: Hematuria
  description: Gross or microscopic hematuria may occur, particularly with more locally advanced disease.
  phenotype_term:
    preferred_term: Hematuria
    term:
      id: HP:0000790
      label: Hematuria
  evidence:
  - reference: PMID:41134363
    reference_title: 'Prostatic artery embolization for palliative control of hematuria in locally advanced or metastatic prostate cancer: a systematic review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prostatic artery embolization (PAE) has emerged as a minimally invasive option for the palliative control of hematuria in locally advanced or metastatic prostate cancer."
    explanation: This supports hematuria as a clinically significant manifestation of locally advanced or metastatic prostate cancer.
- category: Musculoskeletal
  name: Bone Pain
  description: >-
    Bone pain is a characteristic complication of metastatic spread and often
    signals advanced disease with skeletal involvement.
  phenotype_term:
    preferred_term: Bone pain
    term:
      id: HP:0002653
      label: Bone pain
  evidence:
  - reference: PMID:39169855
    reference_title: 'Role of osteoclast inhibitors in prostate cancer bone metastasis; a narrative review.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prostate cancer metastasizes most commonly to the skeleton thus leading to significant morbidity ranging from pain, pathological fractures to spinal cord compression and are the primary cause of patient disability and reduced quality of life."
    explanation: This supports bone pain as a characteristic morbidity of skeletal metastasis in prostate cancer.
- category: Constitutional
  name: Fatigue
  description: Fatigue accompanies advanced disease burden, anemia, and systemic therapy effects.
  phenotype_term:
    preferred_term: Fatigue
    term:
      id: HP:0012378
      label: Fatigue
  evidence:
  - reference: PMID:39761938
    reference_title: 'Efficacy and safety of PARP inhibitors in prostate cancer: An umbrella review of systematic reviews and meta-analyses.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PARPi therapies increased the incidence of adverse events (AEs), including fatigue, nausea, anemia, neutropenia, and thrombocytopenia."
    explanation: This supports fatigue (alongside anemia) as a systemic therapy effect in prostate cancer, consistent with fatigue as a treatment-related manifestation.
- category: Musculoskeletal
  name: Back pain
  frequency: FREQUENT
  description: Vertebral metastases may present with back pain and impending cord compression.
  phenotype_term:
    preferred_term: Back pain
    term:
      id: HP:0003418
      label: Back pain
- category: Musculoskeletal
  name: Recurrent fractures
  frequency: OCCASIONAL
  description: Pathologic fractures reflect fragile metastatic bone despite its osteoblastic appearance.
  phenotype_term:
    preferred_term: Recurrent fractures
    term:
      id: HP:0002757
      label: Recurrent fractures
biochemical:
- name: Prostate-Specific Antigen (PSA)
  notes: >-
    PSA remains the core serum biomarker for screening discussions, risk
    stratification, treatment monitoring, and surveillance after therapy.
  evidence:
  - reference: PMID:40063046
    reference_title: "Prostate Cancer: A Review."
    supports: SUPPORT
    snippet: "Recent guidelines encourage shared decision-making for prostate-specific antigen (PSA) screening."
    explanation: This supports PSA as the key biomarker around which screening and early detection decisions are organized.
- name: Plasma testosterone
  context: >-
    Pharmacodynamic marker of androgen deprivation in advanced prostate cancer;
    suppression toward castrate levels indicates reduced androgen ligand drive.
  readouts:
  - target: Androgen Receptor Signaling Dependence
    relationship: PHARMACODYNAMIC_MARKER_OF
    direction: POSITIVE
    endpoint_context: REGULATORY_SURROGATE
    regulatory_endpoint_refs:
    - FDA-SE-adult-cancer-015
    interpretation: >-
      Higher plasma testosterone indicates greater androgen ligand availability
      for AR signaling, whereas effective GnRH-antagonist therapy suppresses
      testosterone as the pharmacodynamic endpoint.
    evidence:
    - reference: PMID:40063046
      reference_title: "Prostate Cancer: A Review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Treatment of metastatic prostate cancer primarily relies on androgen deprivation therapy, most commonly through medical castration with gonadotropin-releasing hormone agonists.
      explanation: >-
        This review supports testosterone suppression through medical castration
        as a central pharmacodynamic mechanism in metastatic prostate cancer.
    - reference: PMID:34771580
      reference_title: "Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR).
      explanation: >-
        This review supports the linked AR-signaling pathograph node that plasma
        testosterone pharmacodynamically reports on.
genetic:
- name: TMPRSS2:ERG
  association: Somatic fusion-driven ETS activation
  notes: >-
    TMPRSS2:ERG fusion defines a major molecular subtype of prostate adenocarcinoma
    and often co-occurs with other structural alterations including PTEN loss.
  evidence:
  - reference: PMID:40165885
    reference_title: 'Exploring therapeutic applications of PTEN, TMPRSS2:ERG fusion, and tumour molecular subtypes in prostate cancer management.'
    supports: SUPPORT
    snippet: "Prostate cancer can be categorised into various risk groups of tumour molecular subtypes grounded in the idea of genomic structural variations connected to TMPRSS2:ERG fusion and loss of PTEN."
    explanation: This directly links TMPRSS2:ERG fusion to prostate cancer molecular subtypes.
- name: PTEN
  gene_term:
    preferred_term: PTEN
    term:
      id: hgnc:9588
      label: PTEN
  association: Somatic loss or deletion
  notes: >-
    PTEN loss relieves restraint on PI3K/AKT signaling and is associated with
    aneuploidy, aggressive pathology, and metastatic progression.
  evidence:
  - reference: PMID:29308088
    reference_title: 'Distinct subtypes of genomic PTEN deletion size influence the landscape of aneuploidy and outcome in prostate cancer.'
    evidence_source: COMPUTATIONAL
    supports: SUPPORT
    snippet: "PTEN homozygous deletions had a significant increase in aneuploidy compared to PTEN tumors without an apparent deletion, and hemizygous deletions showed an intermediate aneuploidy profile."
    explanation: This supports PTEN loss as a biologically consequential event associated with chromosomal instability in prostate cancer.
- name: AR
  gene_term:
    preferred_term: AR
    term:
      id: hgnc:644
      label: AR
  association: Amplification, activating mutation, or splice variant expression during progression
  notes: >-
    Advanced prostate adenocarcinoma frequently reacquires AR signaling through
    overexpression, mutation, or splice variants such as AR-V7.
  evidence:
  - reference: PMID:34771580
    reference_title: 'Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies.'
    supports: SUPPORT
    snippet: "Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR."
    explanation: This abstract sentence directly supports AR reactivation through amplification, mutation, and splice variants in progressive disease.
- name: TP53
  gene_term:
    preferred_term: TP53
    term:
      id: hgnc:11998
      label: TP53
  association: Somatic loss of function
  notes: TP53 loss contributes to lineage plasticity and treatment resistance.
- name: RB1
  gene_term:
    preferred_term: RB1
    term:
      id: hgnc:9884
      label: RB1
  association: Somatic loss of function
  notes: RB1 loss cooperates with TP53 loss in aggressive, dedifferentiated metastatic states.
- name: MITF
  gene_term:
    preferred_term: MITF
    term:
      id: hgnc:7105
      label: MITF
  association: Gain-of-function E318K mutation
  notes: E318K gain-of-function mutation enhances MITF transcriptional activity and may drive aggressive disease phenotypes. Previously implicated in melanoma and renal cell carcinoma, this mutation was first reported in a single case of metastatic prostate adenocarcinoma with high tumor burden and rapid progression.
  evidence:
  - reference: PMID:42220083
    reference_title: "MITF Gain-of-Function Mutation in Metastatic Prostate Cancer: A Rare Finding With Potential Therapeutic Significance."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report the first case of metastatic prostate adenocarcinoma harboring a gain-of-function MITF E318K mutation. The patient presented with high tumor burden, rapid progression, and evidence of tumor heterogeneity. The E318K mutation, previously linked to melanoma and renal cell carcinoma, enhances MITF transcriptional activity and may contribute to aggressive disease behavior."
    explanation: "First documented case of MITF E318K gain-of-function mutation in metastatic prostate cancer, expanding understanding of MITF's role in aggressive prostate cancer variants."
treatments:
- name: Radical Prostatectomy
  description: Surgical resection is a standard definitive option for higher-risk localized disease.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: surgical procedure
    term:
      id: NCIT:C15329
      label: Surgical Procedure
  evidence:
  - reference: PMID:40063046
    reference_title: "Prostate Cancer: A Review."
    supports: SUPPORT
    snippet: "For patients with higher-risk disease, radiation therapy or radical prostatectomy are reasonable options"
    explanation: This directly supports radical prostatectomy as a standard treatment option for localized higher-risk disease.
- name: Radiation Therapy
  description: External beam or related radiation approaches are standard definitive therapy for localized disease.
  therapeutic_modality: RADIOTHERAPY
  treatment_term:
    preferred_term: Radiation Therapy
    term:
      id: NCIT:C15313
      label: Radiation Therapy
  evidence:
  - reference: PMID:40063046
    reference_title: "Prostate Cancer: A Review."
    supports: SUPPORT
    snippet: "For patients with higher-risk disease, radiation therapy or radical prostatectomy are reasonable options"
    explanation: The abstract explicitly names radiation therapy as a standard option for higher-risk localized disease.
- name: Androgen Deprivation Therapy
  description: >-
    Medical castration with gonadotropin-releasing hormone pathway suppression is
    the backbone of systemic therapy for metastatic hormone-sensitive disease.
  treatment_term:
    preferred_term: androgen deprivation therapy
    term:
      id: NCIT:C15445
      label: Hormone Therapy
  evidence:
  - reference: PMID:40063046
    reference_title: "Prostate Cancer: A Review."
    supports: SUPPORT
    snippet: "Treatment of metastatic prostate cancer primarily relies on androgen deprivation therapy, most commonly through medical castration with gonadotropin-releasing hormone agonists."
    explanation: This identifies androgen deprivation as the core systemic therapy backbone in metastatic disease.
- name: Abiraterone Acetate
  description: >-
    CYP17-mediated androgen synthesis inhibition improves survival in metastatic
    castration-resistant prostate adenocarcinoma and is also used earlier in metastatic disease.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: abiraterone
      term:
        id: CHEBI:68642
        label: abiraterone
  evidence:
  - reference: PMID:21612468
    reference_title: 'Abiraterone and increased survival in metastatic prostate cancer.'
    supports: SUPPORT
    snippet: "After a median follow-up of 12.8 months, overall survival was longer in the abiraterone acetate-prednisone group than in the placebo-prednisone group (14.8 months vs. 10.9 months; hazard ratio, 0.65; 95% confidence interval, 0.54 to 0.77; P<0.001)."
    explanation: This pivotal trial abstract demonstrates an overall survival benefit for abiraterone in metastatic castration-resistant disease.
- name: Enzalutamide
  description: >-
    Second-generation androgen receptor inhibition is effective across nonmetastatic
    and metastatic castration-resistant settings.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: enzalutamide
      term:
        id: NCIT:C71744
        label: Enzalutamide
  evidence:
  - reference: NCIT:C71744
    reference_title: "Enzalutamide (NCIT)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Enzalutamide | Accepted_Therapeutic_Use_For | - | - | castration-resistant prostate cancer (CRPC)"
    explanation: >-
      NCI Thesaurus asserts accepted therapeutic use of enzalutamide for
      castration-resistant prostate cancer.
  - reference: PMID:30535926
    reference_title: 'Enzalutamide: A Review in Castration-Resistant Prostate Cancer.'
    supports: SUPPORT
    snippet: "Oral enzalutamide (Xtandi®), a second generation androgen receptor inhibitor, is indicated for the treatment of castration-resistant prostate cancer (CRPC) in numerous countries worldwide, with specific indications in this patient population varying between individual countries."
    explanation: This supports enzalutamide as a standard AR-directed therapy for castration-resistant prostate cancer.
- name: Androgen Deprivation plus AR Pathway Inhibition
  description: >-
    Combination systemic therapy pairs androgen deprivation therapy with an
    androgen receptor pathway inhibitor for metastatic hormone-sensitive
    prostate cancer, replacing ADT monotherapy for many fit patients.
  evidence:
  - reference: DOI:10.1200/op-24-00690
    reference_title: Real-World Evidence of Combination Therapy Use in Metastatic Hormone-Sensitive Prostate Cancer in the United States From 2017 to 2023
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with robust clinical trial evidence on the benefits of combining androgen-deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs; abiraterone, apalutamide, darolutamide, and enzalutamide) and/or docetaxel (DOC).
    explanation: This supports ADT intensification with androgen receptor pathway inhibitors as a core systemic treatment pattern in mHSPC.
  - reference: PMID:40315400
    reference_title: "Systemic Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "poly(ADP-ribose) polymerase inhibitors (PARPi), chemotherapeutic agents (docetaxel, cabazitaxel)"
    explanation: The 2025 ASCO mCRPC guideline update lists the systemic therapy classes for metastatic castration-resistant prostate cancer, complementing the AR pathway inhibitors named here.
  treatment_term:
    preferred_term: hormone modifying therapy
    term:
      id: NCIT:C15445
      label: Hormone Therapy
    therapeutic_agent:
    - preferred_term: abiraterone
      term:
        id: CHEBI:68642
        label: abiraterone
    - preferred_term: enzalutamide
      term:
        id: CHEBI:68534
        label: enzalutamide
  target_mechanisms:
  - target: Androgen Receptor Signaling Dependence
    treatment_effect: INHIBITS
    description: ADT and AR pathway inhibitors suppress the androgen receptor axis that remains a central growth dependency in metastatic prostate cancer.
    evidence:
    - reference: DOI:10.1200/op-24-00690
      reference_title: "Real-World Evidence of Combination Therapy Use in Metastatic Hormone-Sensitive Prostate Cancer in the United States From 2017 to 2023"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with robust clinical trial evidence on the benefits of combining androgen-deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs; abiraterone, apalutamide, darolutamide, and enzalutamide) and/or docetaxel (DOC).
      explanation: >-
        Supports combined ADT plus AR pathway inhibition as the systemic therapy
        directed at the persistent androgen-receptor-signaling dependency.
- name: Talazoparib plus Enzalutamide
  description: >-
    PARP inhibitor and androgen receptor inhibitor combination therapy for
    homologous recombination repair gene-mutated metastatic
    castration-resistant prostate cancer.
  evidence:
  - reference: DOI:10.1200/jco.23.02182
    reference_title: "US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
    explanation: FDA approval summary supports talazoparib plus enzalutamide for HRR-mutated first-line mCRPC.
  - reference: PMID:40315400
    reference_title: "Systemic Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer: ASCO Guideline Update."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "For patients with BRCA1/2 alterations who did not receive prior ARPI, the combination of PARPi and ARPI (talazoparib + enzalutamide, olaparib and/or niraparib + abiraterone) has shown clinical benefit."
    explanation: The 2025 ASCO mCRPC guideline update supports the talazoparib-plus-enzalutamide PARPi/ARPI combination in BRCA1/2-altered disease.
  treatment_term:
    preferred_term: targeted therapy
    term:
      id: NCIT:C93352
      label: Targeted Therapy
    therapeutic_agent:
    - preferred_term: talazoparib
      term:
        id: CHEBI:231344
        label: talazoparib
    - preferred_term: enzalutamide
      term:
        id: CHEBI:68534
        label: enzalutamide
  target_mechanisms:
  - target: Androgen Receptor Signaling Dependence
    treatment_effect: INHIBITS
    description: Enzalutamide inhibits AR signaling while talazoparib targets DNA-repair vulnerability in HRR-mutated tumors.
    evidence:
    - reference: DOI:10.1200/jco.23.02182
      reference_title: "US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
      explanation: >-
        The FDA approval of the talazoparib-enzalutamide combination supports
        enzalutamide's inhibition of persistent androgen-receptor signaling
        (alongside talazoparib's HRR-directed synthetic lethality).
  - target: Homologous Recombination Deficiency
    treatment_effect: MODULATES
    description: >-
      Talazoparib is directed at the homologous-recombination-deficient state
      itself: PARP inhibition is synthetically lethal in tumors that cannot repair
      double-strand breaks by homologous recombination, which is why eligibility is
      written around HRR gene alteration.
    evidence:
    - reference: DOI:10.1200/jco.23.02182
      reference_title: "US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
      explanation: >-
        Approval restricted to HRR gene-mutated disease supports directing
        talazoparib at the homologous-recombination-deficient mechanism rather than
        at prostate cancer generally.
- name: Pembrolizumab for MSI-H or dMMR Disease
  description: >-
    Anti-PD-1 checkpoint blockade is a biomarker-selected option for metastatic
    prostate cancers with MSI-H/dMMR biology, where responses are enriched
    relative to TMB-high microsatellite-stable tumors.
  evidence:
  - reference: DOI:10.1158/1078-0432.ccr-23-3403
    reference_title: Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab.
    explanation: This supports biomarker-selected pembrolizumab use in immunotherapy-responsive metastatic prostate cancer subsets.
  treatment_term:
    preferred_term: immunotherapy
    term:
      id: NCIT:C15262
      label: Immunotherapy
    therapeutic_agent:
    - preferred_term: pembrolizumab
      term:
        id: NCIT:C106432
        label: Pembrolizumab
  target_mechanisms:
  - target: Immune-Suppressive Tumor Microenvironment
    treatment_effect: INHIBITS
    description: PD-1 blockade counteracts checkpoint-mediated immune evasion in biomarker-selected tumors with high neoantigen or mismatch-repair burden.
    evidence:
    - reference: DOI:10.1158/1078-0432.ccr-23-3403
      reference_title: "Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab.
      explanation: >-
        Supports biomarker-selected PD-1 blockade (pembrolizumab) as the therapy
        directed at the immune-evasion mechanism in MSI-H/dMMR metastatic
        prostate cancer.
  - target: Mismatch Repair Deficiency and Microsatellite Instability
    treatment_effect: MODULATES
    description: >-
      Mismatch-repair deficiency is the selection criterion rather than the drug
      target: checkpoint blockade is offered because the hypermutated,
      microsatellite-unstable genome this mechanism produces raises neoantigen load.
    evidence:
    - reference: DOI:10.1158/1078-0432.ccr-23-3403
      reference_title: "Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer"
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab.
      explanation: >-
        Candidacy defined by MSI-H/dMMR status supports linking pembrolizumab to the
        mismatch-repair-deficiency mechanism that generates it.
discussions:
- discussion_id: kg_prostate_integrated_mutational_footprint_biomarker_validation
  prompt: >-
    Integrated mutational footprints stratify metastasis risk in primary prostate
    cancer and, in one footprint, separate men who fail later on an AR pathway
    inhibitor than on a taxane. Both results come from retrospective cohorts - the
    treatment result from a target trial emulation over real-world metastatic
    whole-genome data with small subgroups. Does an integrated footprint add risk or
    treatment-selection information beyond Gleason grade group, stage, tumour
    mutational burden and the single-gene biomarkers already in use, when measured
    prospectively?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Replication Stress-Driven Chromosomal Instability
  - pathophysiology#Reactive Oxygen Species-Driven Mutagenesis
  - pathophysiology#CDK12-Associated Non-Canonical Homologous Recombination Impairment
  - pathophysiology#Homologous Recombination Deficiency
  - treatments#Androgen Deprivation plus AR Pathway Inhibition
  rationale: >-
    The gap is not whether these mutational processes exist - the footprints are
    derived from whole-genome data and each carries a driver-gene and
    signature-level aetiology, which is why they are curated as mechanism nodes in
    this entry. It is whether they are usable. Two of the claims that would matter
    clinically rest on designs that cannot settle the question. The metastasis-risk
    associations are from a multivariate model on an observational cohort, so they
    establish independence from the recorded covariates rather than incremental
    value over the decision rule a clinician actually applies. The treatment-selection
    result is a trial emulation, and its authors are explicit that it is hypothesis
    generating with limited subgroup sizes; only seven patients in that cohort
    carried the single-gene alteration the footprint is thought to generalize. There
    is also an ascertainment asymmetry worth stating: the footprints were defined on
    tumours with chromosomal instability and quantified in whole-genome sequencing,
    so a prospective test has to specify how a tumour with low purity, low variant
    burden, or targeted-panel-only sequencing is classified, since roughly a sixth of
    the discovery cohort could not be assigned any mutational process at all.
  evidence:
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "As our trial emulation analyses are retrospective and observational, with limited subgroup sizes, these findings should be viewed as hypothesis generating"
    explanation: >-
      The authors' own characterization of the treatment-selection result as
      hypothesis generating is the basis for curating this as an open gap rather
      than as a predictive biomarker.
  - reference: PMID:42717097
    reference_title: Integrated signatures define mutational processes in prostate cancer.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we showed that IMF6 activity was predictive of reduced risk of treatment failure following ARPI"
    explanation: >-
      States the treatment-selection finding whose prospective confirmation this gap
      asks for.
- discussion_id: hmm_prostate_microbial_androgen_biosynthesis_castration_resistance
  prompt: >-
    In mice, gut commensals expand under androgen deprivation and supply an
    alternative source of active androgens: antibiotic ablation of the gut
    microbiota delays the emergence of castration resistance, and fecal
    transplant from castration-resistant donors confers it. In humans the same
    axis is so far only an association - the intestinal community of patients
    with castration-resistant prostate cancer is enriched for
    androgen-converting species, with no interventional human evidence. Does
    microbial
    androgen biosynthesis contribute to castration resistance in human prostate
    cancer, or is the mouse dependency amplified by a host in which adrenal
    androgen production is negligible?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Androgen Receptor Signaling Dependence
  - pathophysiology#Signaling Bypass and Castration Resistance
  - treatments#Androgen Deprivation Therapy
  rationale: >-
    This entry curates castration resistance as a tumor-intrinsic bypass - AR
    amplification, AR splice variants, and intratumoral steroidogenesis. The
    mouse evidence adds a host-external route the pathograph does not represent:
    the gut community itself converting circulating androgen precursors into
    active androgens, restoring ligand to the receptor the therapy was meant to
    starve. What keeps this from being curated as a mechanism node is a
    species difference that is mechanistically load-bearing rather than
    incidental. Mice produce little adrenal androgen, so a microbial
    precursor-conversion route faces little host competition there; in castrated
    men, adrenal DHEA and androstenedione remain a substantial precursor pool
    that intratumoral steroidogenesis already exploits, which is the rationale
    for abiraterone. A microbial contribution in humans therefore has to be
    shown to be non-redundant with a pathway this entry already models, not
    merely present. The human data reported alongside the mouse experiments are
    observational, and the cross-disease review that prompted this discussion
    still describes microbial metabolism of host hormonal precursors as
    hypothesized rather than established for endocrine-therapy resistance. Until
    a human intervention separates the two sources, an edge from a microbial
    node into castration resistance would assert translational validity that the
    evidence does not yet carry.
  proposed_experiments:
  - experiment_id: exp_prostate_microbial_androgen_conversion_human_intervention
    name: Human test of whether gut microbial androgen conversion is non-redundant with adrenal precursor supply
    description: >-
      In men starting androgen deprivation therapy, serially profile the fecal
      metagenome for androgen-converting gene content alongside serum and fecal
      steroid metabolomics, and test whether microbial conversion capacity
      predicts time to castration resistance independently of adrenal precursor
      levels. Nest a randomized microbiota-directed intervention (a
      narrow-spectrum antimicrobial or defined live biotherapeutic selected
      against the converting taxa) within the cohort, stratified by baseline
      adrenal androgen level, so that a microbial effect can be distinguished
      from the adrenal-precursor route that abiraterone already targets.
    experiment_type:
      preferred_term: randomized microbiota-directed intervention nested in a prospective cohort
    readouts:
    - name: Microbial androgen-conversion capacity and time to castration resistance
      target: pathophysiology#Signaling Bypass and Castration Resistance
      description: >-
        Association between baseline and on-treatment fecal androgen-converting
        gene content and time to biochemical castration resistance, adjusted for
        serum adrenal androgen precursors.
      assays:
      - preferred_term: shotgun metagenomic sequencing
      - preferred_term: targeted steroid mass spectrometry
    - name: Circulating active androgen after microbiota-directed intervention
      target: pathophysiology#Androgen Receptor Signaling Dependence
      description: >-
        Change in serum testosterone and dihydrotestosterone in the
        intervention arm relative to control, within adrenal-androgen strata.
      assays:
      - preferred_term: targeted steroid mass spectrometry
      direction: DECREASED
    decision_criterion: >-
      Translational validity is supported if microbial androgen-conversion
      capacity predicts earlier castration resistance independently of adrenal
      precursor levels AND the microbiota-directed intervention lowers active
      androgen and delays resistance in men with low adrenal androgen output. It
      is not supported if the association disappears after adjustment for
      adrenal precursors, or if the intervention alters community composition
      without changing androgen levels or outcome - in which case the mouse
      result should stay flagged as model-specific.
    would_support:
    - pathophysiology#Signaling Bypass and Castration Resistance
  evidence:
  - reference: PMID:34618582
    reference_title: "Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Ablation of the gut microbiota by antibiotic therapy delayed the emergence
      of castration resistance even in immunodeficient mice.
    explanation: >-
      The causal arm of the claim, and it is entirely murine: removing the
      microbiota changes the timing of castration resistance in mice.
  - reference: PMID:34618582
    reference_title: "Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Fecal microbiota transplantation (FMT) from CRPC mice and patients
      rendered mice harboring prostate cancer resistant to castration.
    explanation: >-
      Transfer experiment establishing sufficiency - but the readout organism is
      the mouse, including for the human-donor material, so it does not close
      the translational question.
  - reference: PMID:34618582
    reference_title: "Commensal bacteria promote endocrine resistance in prostate cancer through androgen biosynthesis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Specifically, the intestinal microbial community in mice and patients with
      CRPC was enriched for species capable of converting androgen precursors
      into active androgens.
    explanation: >-
      The human arm of the finding. The quoted sentence spans both mouse and
      patient cohorts and is tagged here for its human component, which is
      observational enrichment only - no human intervention was performed.
  - reference: PMID:42426614
    reference_title: "Microbiota-mediated modulation of the tumor microenvironment in urological cancers: crosstalk between gut and intratumoral microbiota."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Microbial metabolic pathways are also implicated in therapeutic
      resistance; microbial metabolism of host hormonal precursors is
      hypothesized as one mechanism contributing to resistance to endocrine
      therapies.
    explanation: >-
      A 2026 cross-disease review still frames this route as hypothesized rather
      than established for endocrine-therapy resistance, which is the
      field-level statement of the mismatch recorded here.
  notes: >-
    Recorded from monarch-initiative/dismech#6383. Typed HUMAN_MODEL_MISMATCH
    rather than KNOWLEDGE_GAP because the evidence is not absent - it is strong
    and causal in mice, and the open question is whether it transfers to human
    castration resistance. The PMID:42426614 item carries `evidence_source:
    OTHER` because that publication is a narrative review making a field-level
    synthesis claim rather than reporting primary data; see
    monarch-initiative/dismech#8184.
definitions:
- name: 13-CMB AI morphometric predictor of neoadjuvant ADT response
  definition_type: PHENOTYPE_ALGORITHM
  derivation_basis: ESTABLISHED_CRITERIA
  description: >-
    A computable, image-derived predictor that classifies a prostate
    adenocarcinoma needle biopsy as a likely responder or non-responder to
    neoadjuvant androgen deprivation therapy (NADT) — the terminology used in
    the source publication. Inputs are the abundance
    levels of 13 cellular morphometric biomarkers (CMBs) — unsupervised,
    machine-learned cell-appearance prototypes extracted from H&E whole-slide
    images by the CMB-ML pipeline (stacked predictive sparse decomposition), NOT
    named histopathology findings — combined by a LASSO regression into a
    continuous treatment-resistance score that is dichotomized into responder
    versus non-responder. The predictor operationalizes the split
    that this entry's "Signaling Bypass and Castration Resistance" node captures:
    the non-responder state it flags converges on PI3K/AKT/mTORC1-hyperactive
    adaptive resistance (see conforms_to on that node,
    mtor_androgen_deprivation_resistance), which is why it also predicts
    potential benefit from adding an mTOR inhibitor in non-responders.
  scope: >-
    Research-grade, imaging-derived treatment-response predictor from routine
    H&E needle-biopsy whole-slide images. This is NOT an OHDSI/OMOP EHR
    case-finding query and NOT a consensus/validated clinical phenotype; it is a
    published AI biomarker validated retrospectively across independent cohorts.
    The 13 CMBs are latent learned features (cluster prototypes), so they are not
    individually ontology-mappable to NCIT histopathology terms; the biological
    correlates and the mTOR-resistance mechanism are what carry ontology grounding
    (on the pathophysiology nodes and the conformed module).
  attaches_to:
  - pathophysiology#Signaling Bypass and Castration Resistance
  validation_status:
    status: UNVALIDATED
    rationale: >-
      Executed and evaluated against treatment-response and outcome reference
      standards across four cohorts, but not against a prospective/consensus gold
      standard, so it is beyond PROPOSED yet short of VALIDATED_AGAINST_GOLD_STANDARD.
      Reported performance: AUC 0.981 for NADT-plus-enzalutamide response in the
      NCT02430480 training cohort (n = 37); significant stratification of pathologic
      complete response (p = 0.0005) and biochemical recurrence-free survival
      (p = 0.024) in an independent hospital cohort (n = 122); BCRFS (p = 0.031) in a
      second hospital cohort (n = 60); and progression-free survival (p = 0.0017) in
      TCGA-PRAD (n = 396), remaining significant and independent after adjustment
      for established clinical factors and the Decipher and Oncotype DX genomic
      biomarkers. Key limitations that keep it UNVALIDATED as a clinical assay:
      small training cohort (n = 37); validation confined to two independent
      hospital cohorts plus a public genomic cohort; and no prospective evaluation
      reported, the publication positioning the model as one that "could
      potentially serve as a robust solution for precision management".
  evidence:
  - reference: PMID:41887393
    reference_title: "AI-discovered cellular morphometric biomarkers in needle biopsy of prostate cancer predict neoadjuvant androgen deprivation therapy response and enable therapeutic targeting of mTOR in androgen deprivation therapy-resistant tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we identified 13 cellular morphometric biomarkers (CMBs), as a New Approach
      Methodology (NAM), from whole slide images of needle biopsies in clinical
      trial specimens (NCT02430480, n = 37) that accurately predicted response to
      neoadjuvant androgen deprivation therapy (NADT) plus enzalutamide
    explanation: >-
      Establishes the 13-CMB LASSO model as an AI predictor of NADT response
      derived from H&E whole-slide images of needle biopsies in the trial cohort.
  - reference: PMID:41887393
    reference_title: "AI-discovered cellular morphometric biomarkers in needle biopsy of prostate cancer predict neoadjuvant androgen deprivation therapy response and enable therapeutic targeting of mTOR in androgen deprivation therapy-resistant tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the 13-CMB model stratified PCa patients into responders and non-responders
      after NADT across two independent hospital cohorts.
    explanation: >-
      Supports independent-cohort validation of the responder/non-responder
      stratification this definition operationalizes.
  - reference: PMID:41887393
    reference_title: "AI-discovered cellular morphometric biomarkers in needle biopsy of prostate cancer predict neoadjuvant androgen deprivation therapy response and enable therapeutic targeting of mTOR in androgen deprivation therapy-resistant tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      the 13-CMB model demonstrated significant and independent clinical value
      after adjustment for established clinical factors and commonly used genomic
      biomarkers, including Decipher and Oncotype DX.
    explanation: >-
      Supports the claim that the predictor adds value independent of standard
      clinical factors and the Decipher/Oncotype DX genomic assays.
  - reference: PMID:41887393
    reference_title: "AI-discovered cellular morphometric biomarkers in needle biopsy of prostate cancer predict neoadjuvant androgen deprivation therapy response and enable therapeutic targeting of mTOR in androgen deprivation therapy-resistant tumors."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CMBs accurately predicted the molecular differences between stratified
      patient groups and the potential benefit from mTOR inhibitors in
      non-responders, which were validated through IHC staining and
      patient-derived organoids (n = 8), respectively.
    explanation: >-
      Grounds the attaches_to link to the resistance node and the
      mtor_androgen_deprivation_resistance module: the non-responder
      state predicts benefit from mTOR inhibition, validated by IHC and
      patient-derived organoids.
  notes: >-
    Schema-fit caveat (design-register item): dismech's derivation_basis enum has
    no value for an empirically-derived AI/imaging predictor. ESTABLISHED_CRITERIA
    is used here under its "validated computable phenotype" clause because the
    model is a published, cohort-validated computable predictor; its research-grade,
    not-yet-gold-standard maturity is carried separately (and honestly) by
    validation_status: UNVALIDATED. definition_type PHENOTYPE_ALGORITHM is likewise
    the closest available bucket — the model is a computable predictive algorithm,
    but on H&E whole-slide-image features rather than OMOP/EHR case-finding logic,
    so it cannot be expressed as inline criteria_sets. Provenance: Yan et al.,
    Cancer Letters 647 (2026) 218447, doi:10.1016/j.canlet.2026.218447, trial
    NCT02430480. A dedicated imaging/ML-biomarker definition_type and an
    EMPIRICAL_MODEL derivation_basis are proposed follow-ups for the design register.
notes: >-
  Localized prostate adenocarcinoma is frequently indolent enough for risk-adapted
  surveillance, but progression can produce metastatic and castration-resistant
  states with strong bone tropism and increasing pathway heterogeneity. The
  former Metastatic_Prostate_Cancer entry was folded into this entry's Metastatic
  stage (design decisions §3a);
  [`BRCA_Mutant_Prostate_Cancer.yaml`](kb/disorders/BRCA_Mutant_Prostate_Cancer.yaml)
  remains a separate molecularly defined entry.
  The seven mutational-process nodes (AR-mediated mutagenesis, replication stress,
  reactive oxygen species, canonical and CDK12-associated non-canonical homologous
  recombination impairment, mismatch-repair deficiency, APOBEC) curate the
  aetiologies behind the disease's genomic heterogeneity rather than its growth
  signalling, and are drawn from one whole-genome cohort study. They are the
  mechanisms that generate diversity; the entry's other nodes are the traits
  selected from it.
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0005082
      label: prostate adenocarcinoma
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: MONDO provides an exact disease term for prostate adenocarcinoma; this is the same term used as `disease_term` for this entry.
  - term:
      id: MONDO:0004956
      label: metastatic prostate carcinoma
    mapping_predicate: skos:narrowMatch
    mapping_source: MONDO
    mapping_justification: >-
      MONDO's dedicated metastatic prostate carcinoma entity corresponds to the
      Metastatic stage of this entry (the former Metastatic_Prostate_Cancer
      entry, folded in per design decisions §3a).
  ncit_mappings:
  - term:
      id: NCIT:C2919
      label: Prostate Adenocarcinoma
    mapping_predicate: skos:exactMatch
    mapping_source: NCIT
    mapping_justification: NCIT provides an exact concept for prostate adenocarcinoma; MONDO:0005082 cross-references NCIT:C2919 in its xref list.
classifications:
  icdo_morphology:
    classification_value: Adenocarcinoma
  harrisons_chapter:
  - classification_value: ONCOLOGY_HEMATOLOGY
datasets:
- accession: ega:EGAS00001000451
  title: Plasma-Seq of patients with metastatic prostate cancer
  description: Study 1 In this study we analysed patients with metastatic prostate cancer to scan their tumor genomes noninvasively in plasma DNA. We wanted to make whole-genome analysis from plasma DNA amenable to clinical routine applications and developed an approach based on a benchtop high-throughput platform, i.e. Illuminas MiSeq instrument. We performed whole-genome sequencing from plasma at a shallow sequencing depth to establish a genome-wide copy number profile of the tumor at low costs within 2 days. The genome-wide profiling in the plasma of our patients revealed multiple copy number aberrations including those previously reported in prostate tumors, such as losses in 8p and gains in 8q.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  publication: PMID:23561577
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Metastatic Prostate Cancer"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001000453
  title: Identification of mutations and structural rearrangements in plasma DNA form metastatic prostate cancer patients
  description: 'In this study we analysed patients with metastatic prostate cancer to scan their tumor genomes noninvasively in plasma DNA. We enriched 1.3 Mbp of seven plasma DNAs (4 CRPC cases: CRPC1-3 and CRPC5; 3 CSPC cases: CSPC1-2 and CSPC4) including exonic sequences of 55 cancer genes and 38 introns of 18 genes, where fusion breakpoints have been described using Sure Select Custom DNA Kit.'
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Metastatic Prostate Cancer"); description-level mentions were not accepted. EGA study_type: Resequencing. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
- accession: ega:EGAS00001001018
  title: Whole-genome plasma sequencing reveals focal amplifications as a driving force in metastatic prostate cancer
  description: Genomic alterations in metastatic prostate cancer remain incompletely characterized. Here we analyze 493 prostate cancer cases from the TCGA database and perform whole-genome plasma sequencing on 95 plasma samples derived from 43 patients with metastatic prostate cancer. From these samples, we identify established driver aberrations in a cancer-related gene in nearly all cases (97.7%), including driver gene fusions (TMPRSS2:ERG), driver focal deletions (PTEN, RYBP, SHQ1), and driver amplifications (AR, MYC). In serial plasma analyses, we observe changes in focal amplifications in 40% of cases.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  notes: 'European Genome-phenome Archive study, matched because the disease is named in the study''s own title ("Metastatic Prostate Cancer"); description-level mentions were not accepted. EGA study_type: Other. Controlled access -- data require a Data Access Agreement. EGA metadata retrieved 2026-08-01.'
references:
- reference: DOI:10.1007/s11864-024-01215-2
  title: 'Metastatic Castration-Resistant Prostate Cancer: Advances in Treatment and Symptom Management'
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: 'Metastatic Castration-Resistant Prostate Cancer: Advances in Treatment and Symptom Management'
    supporting_text: Opinion statementThe management of metastatic castrate-resistant prostate cancer (mCRPC) has evolved in the past decade due to substantial advances in understanding the genomic landscape and biology underpinning this form of prostate cancer.
    evidence:
    - reference: DOI:10.1007/s11864-024-01215-2
      reference_title: 'Metastatic Castration-Resistant Prostate Cancer: Advances in Treatment and Symptom Management'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Opinion statementThe management of metastatic castrate-resistant prostate cancer (mCRPC) has evolved in the past decade due to substantial advances in understanding the genomic landscape and biology underpinning this form of prostate cancer.
      explanation: Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.
- reference: DOI:10.1016/j.eururo.2024.04.010
  title: 'EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II—2024 Update: Treatment of Relapsing and Metastatic Prostate Cancer'
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: 'EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II—2024 Update: Treatment of Relapsing and Metastatic Prostate Cancer'
    supporting_text: 'EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II—2024 Update: Treatment of Relapsing and Metastatic Prostate Cancer'
- reference: DOI:10.1038/s41591-023-02704-x
  title: 'First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial'
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase.
    supporting_text: Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase.
    evidence:
    - reference: DOI:10.1038/s41591-023-02704-x
      reference_title: 'First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase.
      explanation: Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.
- reference: DOI:10.1101/2025.04.15.25325837
  title: 'Systemic treatment options for metastatic castration resistant prostate cancer: A living systematic review'
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: Optimal treatment selection for metastatic castration resistant prostate cancer (mCRPC) remains challenging due to evolving standards of care in castration sensitive setting.
    supporting_text: Optimal treatment selection for metastatic castration resistant prostate cancer (mCRPC) remains challenging due to evolving standards of care in castration sensitive setting.
    evidence:
    - reference: DOI:10.1101/2025.04.15.25325837
      reference_title: 'Systemic treatment options for metastatic castration resistant prostate cancer: A living systematic review'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Optimal treatment selection for metastatic castration resistant prostate cancer (mCRPC) remains challenging due to evolving standards of care in castration sensitive setting.
      explanation: Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.
- reference: DOI:10.1158/1078-0432.ccr-23-3403
  title: Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab.
    supporting_text: Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab.
    evidence:
    - reference: DOI:10.1158/1078-0432.ccr-23-3403
      reference_title: Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab.
      explanation: Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.
- reference: DOI:10.1200/jco.23.02182
  title: 'US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer'
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
    supporting_text: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
    evidence:
    - reference: DOI:10.1200/jco.23.02182
      reference_title: 'US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).
      explanation: Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.
- reference: DOI:10.1200/op-24-00690
  title: Real-World Evidence of Combination Therapy Use in Metastatic Hormone-Sensitive Prostate Cancer in the United States From 2017 to 2023
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: Real-World Evidence of Combination Therapy Use in Metastatic Hormone-Sensitive Prostate Cancer in the United States From 2017 to 2023
    supporting_text: Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with robust clinical trial evidence on the benefits of combining androgen-deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs; abiraterone, apalutamide, darolutamide, and enzalutamide) and/or docetaxel (DOC).
    evidence:
    - reference: DOI:10.1200/op-24-00690
      reference_title: Real-World Evidence of Combination Therapy Use in Metastatic Hormone-Sensitive Prostate Cancer in the United States From 2017 to 2023
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with robust clinical trial evidence on the benefits of combining androgen-deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs; abiraterone, apalutamide, darolutamide, and enzalutamide) and/or docetaxel (DOC).
      explanation: Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.
- reference: DOI:10.3322/caac.70028
  title: Prostate cancer statistics, 2025
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: Prostate cancer is the most common cancer among men in the United States, and the incidence of advanced disease is increasing rapidly.
    supporting_text: Prostate cancer is the most common cancer among men in the United States, and the incidence of advanced disease is increasing rapidly.
    evidence:
    - reference: DOI:10.3322/caac.70028
      reference_title: Prostate cancer statistics, 2025
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Prostate cancer is the most common cancer among men in the United States, and the incidence of advanced disease is increasing rapidly.
      explanation: Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.
- reference: DOI:10.3390/cancers15061849
  title: Advances in PARP Inhibitors for Prostate Cancer
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair.
    supporting_text: Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair.
    evidence:
    - reference: DOI:10.3390/cancers15061849
      reference_title: Advances in PARP Inhibitors for Prostate Cancer
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair.
      explanation: Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.
- reference: DOI:10.3390/cancers15092552
  title: Management of Advanced Prostate Cancer in the Precision Oncology Era
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: Prostate cancer (PC) is the second leading cause of cancer death in men in the United States.
    supporting_text: Prostate cancer (PC) is the second leading cause of cancer death in men in the United States.
    evidence:
    - reference: DOI:10.3390/cancers15092552
      reference_title: Management of Advanced Prostate Cancer in the Precision Oncology Era
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Prostate cancer (PC) is the second leading cause of cancer death in men in the United States.
      explanation: Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.
- reference: DOI:10.3390/ijms262311665
  title: 'Therapeutic Advances in Metastatic Prostate Cancer: A Journey from Standard of Care to New Emerging Treatment'
  found_in:
  - Metastatic_Prostate_Cancer-deep-research-falcon.md
  findings:
  - statement: Prostate cancer (PCa) remains one of the most prevalent malignancies among men worldwide and continues to pose significant therapeutic challenges, especially in its metastatic and castration-resistant forms.
    supporting_text: Prostate cancer (PCa) remains one of the most prevalent malignancies among men worldwide and continues to pose significant therapeutic challenges, especially in its metastatic and castration-resistant forms.
    evidence:
    - reference: DOI:10.3390/ijms262311665
      reference_title: 'Therapeutic Advances in Metastatic Prostate Cancer: A Journey from Standard of Care to New Emerging Treatment'
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Prostate cancer (PCa) remains one of the most prevalent malignancies among men worldwide and continues to pose significant therapeutic challenges, especially in its metastatic and castration-resistant forms.
      explanation: Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.
review_notes: >-
  From the folded Metastatic_Prostate_Cancer entry: its environmental section was
  removed. Its only entry was "Older age", which is a property of the patient
  rather than something the patient is exposed to, and which ECTO and XCO have no
  term for by design. Per dismech#8551 an age association belongs in a prevalence
  population stratifier; the entry carried no citation to carry across, so nothing
  was migrated and no new claim was manufactured.

  The mutational-process nodes deliberately carry no `genetic_context`. Each is a
  process-level bias in where and how mutations arise rather than a single somatic
  variant, and a `variant_origin: SOMATIC` block on any of them would be read by
  the cancer-cell-of-origin derivation as a second transforming lesion competing
  with the ETS-fusion node. Their driver-gene associations (BRCA2, CDK12, MSH2,
  SPOP) are carried in prose and evidence instead.

  Their source was curated ahead of PubMed indexing, as
  `DOI:10.1038/s41586-026-10468-w`, whose Crossref record carries no abstract; the
  snippets were transcribed from the publisher PDF and could not then be checked
  by tooling. The paper is now `PMID:42717097` with full text cached, every
  snippet was re-cited against it, and all 28 verify as exact substrings with no
  hyphenation tolerance. Cite the PMID, not the DOI.

📚

References & Deep Research

References

11

DOI:10.1007/s11864-024-01215-2

Metastatic Castration-Resistant Prostate Cancer: Advances in Treatment and Symptom Management

1 finding

Metastatic Castration-Resistant Prostate Cancer: Advances in Treatment and Symptom Management

"Opinion statementThe management of metastatic castrate-resistant prostate cancer (mCRPC) has evolved in the past decade due to substantial advances in understanding the genomic landscape and biology underpinning this form of prostate cancer."

Show evidence (1 reference)

DOI:10.1007/s11864-024-01215-2 SUPPORT Other

"Opinion statementThe management of metastatic castrate-resistant prostate cancer (mCRPC) has evolved in the past decade due to substantial advances in understanding the genomic landscape and biology underpinning this form of prostate cancer."

Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.

DOI:10.1016/j.eururo.2024.04.010

EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II—2024 Update: Treatment of Relapsing and Metastatic Prostate Cancer

1 finding

EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II—2024 Update: Treatment of Relapsing and Metastatic Prostate Cancer

"EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II—2024 Update: Treatment of Relapsing and Metastatic Prostate Cancer"

DOI:10.1038/s41591-023-02704-x

First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial

1 finding

Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase.

"Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase."

Show evidence (1 reference)

DOI:10.1038/s41591-023-02704-x SUPPORT Human Clinical

"Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase."

Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.

DOI:10.1101/2025.04.15.25325837

Systemic treatment options for metastatic castration resistant prostate cancer: A living systematic review

1 finding

Optimal treatment selection for metastatic castration resistant prostate cancer (mCRPC) remains challenging due to evolving standards of care in castration sensitive setting.

"Optimal treatment selection for metastatic castration resistant prostate cancer (mCRPC) remains challenging due to evolving standards of care in castration sensitive setting."

Show evidence (1 reference)

DOI:10.1101/2025.04.15.25325837 Preprint · not peer-reviewed SUPPORT Other

"Optimal treatment selection for metastatic castration resistant prostate cancer (mCRPC) remains challenging due to evolving standards of care in castration sensitive setting."

Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.

DOI:10.1158/1078-0432.ccr-23-3403

Microsatellite Instability, Tumor Mutational Burden, and Response to Immune Checkpoint Blockade in Patients with Prostate Cancer

1 finding

Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab.

"Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab."

Show evidence (1 reference)

DOI:10.1158/1078-0432.ccr-23-3403 SUPPORT Human Clinical

"Patients with microsatellite instability–high/mismatch repair-deficient (MSI-H/dMMR) and high tumor mutational burden (TMB-H) prostate cancers are candidates for pembrolizumab."

Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.

DOI:10.1200/jco.23.02182

US Food and Drug Administration Approval Summary: Talazoparib in Combination With Enzalutamide for Treatment of Patients With Homologous Recombination Repair Gene-Mutated Metastatic Castration-Resistant Prostate Cancer

1 finding

The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC).

"The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC)."

Show evidence (1 reference)

DOI:10.1200/jco.23.02182 SUPPORT Human Clinical

"The US Food and Drug Administration (FDA) approved talazoparib with enzalutamide for first-line treatment of patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC)."

Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.

DOI:10.1200/op-24-00690

Real-World Evidence of Combination Therapy Use in Metastatic Hormone-Sensitive Prostate Cancer in the United States From 2017 to 2023

1 finding

Real-World Evidence of Combination Therapy Use in Metastatic Hormone-Sensitive Prostate Cancer in the United States From 2017 to 2023

"Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with robust clinical trial evidence on the benefits of combining androgen-deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs; abiraterone, apalutamide, darolutamide, and enzalutamide) and/or..."

Show evidence (1 reference)

DOI:10.1200/op-24-00690 SUPPORT Human Clinical

"Treatment of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with robust clinical trial evidence on the benefits of combining androgen-deprivation therapy (ADT) with androgen receptor pathway inhibitors (ARPIs; abiraterone, apalutamide, darolutamide, and enzalutamide) and/or..."

Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.

DOI:10.3322/caac.70028

Prostate cancer statistics, 2025

1 finding

Prostate cancer is the most common cancer among men in the United States, and the incidence of advanced disease is increasing rapidly.

"Prostate cancer is the most common cancer among men in the United States, and the incidence of advanced disease is increasing rapidly."

Show evidence (1 reference)

DOI:10.3322/caac.70028 SUPPORT Human Clinical

"Prostate cancer is the most common cancer among men in the United States, and the incidence of advanced disease is increasing rapidly."

Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.

DOI:10.3390/cancers15061849

Advances in PARP Inhibitors for Prostate Cancer

1 finding

Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair.

"Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair."

Show evidence (1 reference)

DOI:10.3390/cancers15061849 SUPPORT Other

"Poly-adenosine diphosphate-ribose polymerase plays an essential role in cell function by regulating apoptosis, genomic stability and DNA repair."

Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.

DOI:10.3390/cancers15092552

Management of Advanced Prostate Cancer in the Precision Oncology Era

1 finding

Prostate cancer (PC) is the second leading cause of cancer death in men in the United States.

"Prostate cancer (PC) is the second leading cause of cancer death in men in the United States."

Show evidence (1 reference)

DOI:10.3390/cancers15092552 SUPPORT Other

"Prostate cancer (PC) is the second leading cause of cancer death in men in the United States."

Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.

DOI:10.3390/ijms262311665

Therapeutic Advances in Metastatic Prostate Cancer: A Journey from Standard of Care to New Emerging Treatment

1 finding

Prostate cancer (PCa) remains one of the most prevalent malignancies among men worldwide and continues to pose significant therapeutic challenges, especially in its metastatic and castration-resistant forms.

"Prostate cancer (PCa) remains one of the most prevalent malignancies among men worldwide and continues to pose significant therapeutic challenges, especially in its metastatic and castration-resistant forms."

Show evidence (1 reference)

DOI:10.3390/ijms262311665 SUPPORT Other

"Prostate cancer (PCa) remains one of the most prevalent malignancies among men worldwide and continues to pose significant therapeutic challenges, especially in its metastatic and castration-resistant forms."

Deep research cited this publication as relevant literature for Metastatic Prostate Cancer.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Asta ▸

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Prostate Adenocarcinoma. Core disease mechanisms, molecular and cellular p...

Asta Scientific Corpus Retrieval 20 citations 2026-04-11T22:12:54.428569

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Prostate Adenocarcinoma. Core disease mechanisms, molecular and cellular p...

This report is retrieval-only and is generated directly from Asta results.

Papers retrieved: 20
Snippets retrieved: 20

Relevant Papers

[1] Inflammatory Microenvironment in Prostate Carcinogenesis

Authors: G. Gueron, J. Cotignola, E. Vazquez
Year: 2013
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/296dbc4e031505eb847327aef24cb42c32b9c3b5
DOI: 10.5772/52636
Citations: 1
Summary: In this synopsis, blocking the sus‐ tained inflammatory network will offer new promising avenues to achieve significant therapeutic gains in the treatment of prostate cancer.
Evidence snippets:
Snippet 1 (score: 0.483) > The association between prostate cancer and inflammation was first formally addressed in the nineteen century and since then many authors have confirmed the biological and clinical evidence of this association. However, the molecular mechanism involved is yet to be deciphered. > There are two well established pathways linking inflammation and cancer: the extrinsic pathway from conditions that cause non-resolving smouldering inflammatory responses and the intrinsic pathway where the misregulation of oncogenes and tumor suppressor genes switch on the expression of inflammation-related programs. > Prostate cancer is a complex and progressive disease. Over time the cells become resistance to hormonal therapies that are designed to block the release and/or the uptake of androgens. During this stage androgen receptor (AR) mutants are able to bind promiscuous steroids, and may convert AR antagonists to agonists. Other hormones and their receptors are involved in the abnormal growth of the gland. Particularly, oestrogens and oestrogen receptors defined a subclass of prostate cancer with a very aggressive clinical phenotype (such as the TMPRSS2-ERG fusion). In addition, other signaling cascades are switched on bypassing the androgen/AR axis and favoring tumor progression. Among them, cyclooxygenase-2 (COX-2), neuroendocrine differentiation and the loss of the tumor suppressor phosphatase and tensin homolog (PTEN), with the concomitant inhibition of the PI3K/Akt, resulting in Bcl-2 overexpression and the burst of pro-inflammatory cytokines, chemokines and other growth factors production, contributing all to the progression to the hormonal-resistance disease. As in other malignancies in prostate cancer, reactive oxygen species (ROS) cause ox-idative damage to macromolecules in epithelial cells and can react with other cellular components initiating a free radical chain reaction, thus sustaining the prostate carcinogenic process and its progression. > The molecular mechanisms that prime the pathogenesis of cancer-related inflammation are complex and involve a delicate interplay between tumor and its microenvironment. In prostate tumors, the switch to an angiogenic phenotype is known to be critical for its progression.

[2] РАК ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ, СОВРЕМЕННЫЕ ТЕРАПЕВТИЧЕСКИЕ ПОДХОДЫ И ВОЗМОЖНЫЕ ПЕРСПЕКТИВЫ

Authors: Елена Александровна Быкова, Н. А. Фалалеева, Л. Ю. Гривцова
Year: 2020
Venue: Unknown venue
URL: https://www.semanticscholar.org/paper/8644d81c21f69f5c6cb3cd2e102091f425ab5eb6
DOI: 10.17650/1726-9784-2020-19-4-18-28
Citations: 8
Summary: It is likely that in the future, the integration of traditional chemotherapeutic treatments and an immunological approach will be the key to effective treatment of this deadly disease.
Evidence snippets:
Snippet 1 (score: 0.476) > Prevalence of pancreatic cancer (PC) is not high in the population, but the aggressive nature of the disease leads to the fact that PC is one of the main causes of death in a group of patients with cancer. The prognosis for PC is significantly worse in the case of metastatic spread. It is proved that pancreatic adenocarcinoma from the very beginning is a systemic disease with early micrometastatic spread, so the question of effective drug treatment is extremely relevant. Chemotherapy is the basis for the treatment of patients with metastatic prostate cancer. However, despite numerous clinical studies using known cytostatic and targeted agents, progress in the treatment of this disease remains relatively modest compared to the progress made in the treatment of other types of tumors. The complexities of prostate cancer therapy are explained by the presence of a dense connective tissue tumor stroma, which is not just a barrier to tumor cells. It has a significant impact on various vital cellular processes, including tumor formation, invasion, metastasis, and contributes to the formation of drug resistance. Pancreatic cancer is heterogeneous in terms of molecular and biological characteristics. Many genetic changes, including germ lines and somatic mutations, contribute to the development of this disease. Recent studies have shown that each sample of prostate cancer includes an average of 63 genetic changes and 12 major signalling pathways. Further studies of tumor microenvironment markers and decoding the heterogeneity of the tumor genome in PC should become the basis for a “personalized” approach to treatment. It is likely 19 4'2020 ТОм 19 vol. 19 РОССИЙСКИЙ БИОТЕРАПЕВТИЧЕСКИЙ ЖУРНАЛ Russian journal of biotherapy Обзоры литературы that in the future, the integration of traditional chemotherapeutic treatments and an immunological approach will be the key to effective treatment of this deadly disease.

[3] PANCREATIC CANCER, CURRENT THERAPEUTIC APPROACHES AND POSSIBLE PROSPECTS

Authors: E. A. Bykova, N. Falaleeva, L. Grivtsova
Year: 2020
Venue: Russian Journal of Biotherapy
URL: https://www.semanticscholar.org/paper/3787251a542af30dfbc259e7fa2d906b1438b3f8
DOI: 10.17650/1726-9784-2020-19-4-18-28
Summary: It is likely that in the future, the integration of traditional chemotherapeutic treatments and an immunological approach will be the key to effective treatment of this deadly disease.
Evidence snippets:
Snippet 1 (score: 0.476) > Prevalence of pancreatic cancer (PC) is not high in the population, but the aggressive nature of the disease leads to the fact that PC is one of the main causes of death in a group of patients with cancer. The prognosis for PC is significantly worse in the case of metastatic spread. It is proved that pancreatic adenocarcinoma from the very beginning is a systemic disease with early micrometastatic spread, so the question of effective drug treatment is extremely relevant. Chemotherapy is the basis for the treatment of patients with metastatic prostate cancer. However, despite numerous clinical studies using known cytostatic and targeted agents, progress in the treatment of this disease remains relatively modest compared to the progress made in the treatment of other types of tumors. The complexities of prostate cancer therapy are explained by the presence of a dense connective tissue tumor stroma, which is not just a barrier to tumor cells. It has a significant impact on various vital cellular processes, including tumor formation, invasion, metastasis, and contributes to the formation of drug resistance. Pancreatic cancer is heterogeneous in terms of molecular and biological characteristics. Many genetic changes, including germ lines and somatic mutations, contribute to the development of this disease. Recent studies have shown that each sample of prostate cancer includes an average of 63 genetic changes and 12 major signalling pathways. Further studies of tumor microenvironment markers and decoding the heterogeneity of the tumor genome in PC should become the basis for a “personalized” approach to treatment. It is likely 19 4'2020 ТОм 19 vol. 19 РОССИЙСКИЙ БИОТЕРАПЕВТИЧЕСКИЙ ЖУРНАЛ Russian journal of biotherapy Обзоры литературы that in the future, the integration of traditional chemotherapeutic treatments and an immunological approach will be the key to effective treatment of this deadly disease.

[4] Immunotherapy in prostate cancer: new horizon of hurdles and hopes

Authors: I. Tsaur, M. Brandt, E. Juengel, C. Manceau, G. Ploussard
Year: 2020
Venue: World Journal of Urology
URL: https://www.semanticscholar.org/paper/8228f5608d543e0f1ae86428238acfded7d91371
DOI: 10.1007/s00345-020-03497-1
PMID: 33106940
PMCID: 8514362
Citations: 28
Influential citations: 1
Summary: Current evidence, based on cellular and molecular conditions, encourages further research in this field and highlights the underlying cellular mechanisms crucial for IT in PCa and gives an update of the most essential past and ongoing clinical trials in the field.
Evidence snippets:
Snippet 1 (score: 0.468) > Prostate cancer (PCa) is the most common malignancy in men and the cause for the second most common cancer-related death in the western world. Despite ongoing development of novel approaches such as second generation androgen receptor targeted therapies, metastatic disease is still fatal. In PCa, immunotherapy (IT) has not reached a therapeutic breakthrough as compared to several other solid tumors yet. We aimed at highlighting the underlying cellular mechanisms crucial for IT in PCa and giving an update of the most essential past and ongoing clinical trials in the field. We searched for relevant publications on molecular and cellular mechanisms involved in the PCa tumor microenvironment and response to IT as well as completed and ongoing IT studies and screened appropriate abstracts of international congresses. Tumor progression and patient outcomes depend on complex cellular and molecular interactions of the tumor with the host immune system, driven rather dormant in case of PCa. Sipuleucel-T and pembrolizumab are the only registered immune-oncology drugs to treat this malignancy. A plethora of studies assess combination of immunotherapy with other agents or treatment modalities like radiation therapy which might increase its antineoplastic activity. No robust and clinically relevant prognostic or predictive biomarkers have been established yet. Despite immunosuppressive functional status of PCa microenvironment, current evidence, based on cellular and molecular conditions, encourages further research in this field.

[5] Castration-Resistant Prostate Cancer: Targeted Therapies and Individualized Treatment

Authors: Rahul Aggarwal, Charles J. Ryan
Year: 2011
Venue: The Oncologist
URL: https://www.semanticscholar.org/paper/fab3031b6a49500f576b8f5ec721d8efb5658787
DOI: 10.1634/theoncologist.2010-0216
PMID: 21339259
PMCID: 3228103
Citations: 33
Influential citations: 1
Summary: Several novel therapies for castration-resistant prostate cancer targeted to androgen receptor–mediated and non–androgen receptor-mediated pathways that have recently entered clinical trials are highlighted.
Evidence snippets:
Snippet 1 (score: 0.462) > Although most men who develop prostate cancer do not die from their disease, those who develop castration-resistant prostate cancer (CRPC) have a poor prognosis and are more likely to die from complications of metastatic disease than from comorbid illness. Approved systemic chemotherapies for CRPC provide limited benefits. Docetaxel, a taxane inhibitor of microtubule function, remains the standard firstline treatment based on two phase III trials that showed a median survival time of 18 -19 months [1,2]. Efforts are ongoing to develop various therapies targeting mechanisms behind tumor progression. Several molecular pathways have been implicated in prostate cancer progression from localized disease that remains sensitive to androgen deprivation to CRPC, the lethal tumor phenotype. Pathways can be divided into those mediated by the androgen receptor (AR) and those without direct agonism of the AR [3]. Novel therapies have been rationally designed to target molecular pathways involved in oncogenesis and disease progression although results from trials have been mixed. The biologic heterogeneity of CRPC, including potential involvement of AR-mediated or AR-independent pathways, is a probable cause of the variable responses seen with targeted therapies. Arguably, a more rational approach could involve determining the biologic status of an individual tumor before therapy by assessing gene expression, hormone metabolism, or signaling activity, and directing treatment accordingly. This more individualized approach is being tested in early-phase clinical trials. > Here, we highlight several novel therapies for CRPC targeted to AR-mediated or non-AR-mediated pathways that have recently entered clinical trials, including the molecular rationale and available clinical data. We also summarize emerging evidence on the potential of individualized therapy for CRPC.

[6] Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?

Authors: Laura A. Sena, S. Denmeade
Year: 2021
Venue: Cancer Research
URL: https://www.semanticscholar.org/paper/6cccb007906263932d78cf7ce1d86fa90a9e8a0a
DOI: 10.1158/0008-5472.CAN-21-1392
PMID: 34145040
PMCID: 8416800
Citations: 50
Influential citations: 2
Summary: Evidence indicating that fatty acid synthesis drives progression of prostate cancer is summarized and explanations for this phenomenon are explored and future directions for targeting this pathway for patient benefit are discussed.
Evidence snippets:
Snippet 1 (score: 0.457) > 20:1n9 or 11) are higher in primary prostate cancer compared with benign prostate, and may be higher still in metastatic prostate cancer (34)(35)(36). Although linoleate is considered an essential polyunsaturated fatty acid (PUFA) that must be taken up by the cell, the remainder of these fatty acids can be synthesized de novo. Conversely, quantity of the fatty acid precursor citrate is reduced in high versus low Gleason score primary prostate cancer, which may indicate high utilization (37,38). Finally, noninvasive molecular imaging techniques using positron emission tomography (PET) also support the concept that prostate cancer engages in de novo fatty acid synthesis. While glucose uptake is generally low in prostate cancer (as assessed by 18 F-fluorodeoxyglucose PET), acetate uptake is higher (as assessed by 11 C-acetate PET) and is predictive of biochemical relapse after prostatectomy (39,40). Acetate uptake seems to be used for de novo fatty acid synthesis because it is diminished by inhibitors of FASN (41,42). > While these data suggest that de novo fatty acid synthesis occurs in human prostate cancer, and with increasing rate with disease progression (Fig. 2D), this could be assessed more definitively using isotope tracing followed by assessment of labeling patterns by mass spectrometry in biopsy samples of patients, as has been performed in patients with renal cell carcinoma (43). Moreover, given that cellular metabolic flux is shaped by both cell-intrinsic factors and the microenvironment (44), future studies should consider how prostate cancer cell rates of fatty acid synthesis are altered depending on composition of surrounding cell types (i.e., anatomic location of the metastasis) and metabolite and oxygen availability. These studies are critically important not only to better define the pathophysiology of prostate cancer, but also to identify biomarkers of high rates of fatty acid synthesis that may predict clinical response to inhibitors of this pathway.

[7] Signalling pathways in a nutshell: from pathogenesis to therapeutical implications in prostate cancer

Authors: A. P. Goncharov, C. Dicusari Elissaiou, E. Ben Aharon Farzalla, Giorgi Akhvlediani, Nino Vashakidze et al.
Year: 2025
Venue: Annals of Medicine
URL: https://www.semanticscholar.org/paper/dc4711ef4df5ade8cec4dffd04d8e085044e0a32
DOI: 10.1080/07853890.2025.2474175
PMID: 40372974
PMCID: 12082737
Citations: 3
Summary: This review will discuss the different signalling pathways, such as TGF-β, Cripto-1, Wnt pathways, Hedgehog, Notch and NF-κB pathways, and how they promote tumour initiation and progression by influencing diverse cellular processes and EMT in general and in benign and malignant prostate tumours.
Evidence snippets:
Snippet 1 (score: 0.448) > Prostate cancer is the second most common tumour in men after skin cancer. It is considered the second most common cause of cancer-related deaths amongst men in the United States and fifth globally [1,2]. Prostate cancer classification and staging systems are based on clinical and laboratory evaluation, as well as imaging and histological classification [3]. > According to treatment response and clinical and histopathological features, tumours may be classified as organ-confined, locally advanced, metastatic castration-sensitive prostate cancer (mCSPC), metastatic castration-resistant prostate cancer (mCRPC), or as a lethal disease [3][4][5]. > mCRPC is further divided into five subgroups according to the histologic characteristics and the expression of androgen receptor (AR) and neuroendocrine (NE) markers: adenocarcinoma (AR + /NE − ), double-positive (AR + /NE + ), low AR (ARL/NE − ), neuroendocrine (AR − /NE + ), and double-negative (AR − /NE − ) [6]. > The treatment lines vary between the types and are directly related to the extent of tumour progression. The epithelial-mesenchymal transition (EMT) is an integral stage in determining the invasive potential, progression, and aggressiveness of the tumour [7]. Our group has previously described the importance of the EMT process and its mechanism of action in benign and malignant prostate tumours. Initiation of the EMT process requires the activation of various signalling pathways within the cell. Later, cells reduce the expression of proteins such as E-cadherin, β-catenin, Desmoplakin, Syndecan, and several others. At the same time, proteins that are related to mesenchymal phenotypes, such as Vimentin, Fibronectin, Snail, and Slug, are upregulated [8]. A harsh tumour environment encourages the utilisation of different mechanisms to promote tumour survival and proliferation. Changes in the tumour microenvironment are essential; therefore, it is important to point out the different mechanisms leading to EMT [9].

[8] Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

Authors: Aasems Jacob, Rishi Raj, Derek B. Allison, Zin W. Myint
Year: 2021
Venue: Cancers
URL: https://www.semanticscholar.org/paper/93d425f8fbbccd8b90f442fbef73e8e7508c3ee3
DOI: 10.3390/cancers13215417
PMID: 34771580
PMCID: 8582395
Citations: 104
Influential citations: 3
Summary: This review article details the current evidence on clinically relevant driver mechanisms, relevant biomarkers, and treatment modalities to overcome resistance of androgen receptor (AR) in prostate cancer.
Evidence snippets:
Snippet 1 (score: 0.439) > Simple Summary Early-stage and castration-sensitive prostate cancer (PCa) growth is solely mediated by androgen signaling pathways. AR signaling inhibitors (ARSIs) have significantly improved clinical outcomes among men with PCa. In the metastatic castration-resistant PCa, there is presence of both androgen-dependent and androgen-independent cells driving the tumor growth. Despite the use of ARSIs, disease progression ultimately occurs in all patients with PCa and is due to genetic alterations in ARs, resulting in the outgrowth of androgen-independent cells. The possible mechanisms include development of AR splice variants of which AR-V7 is more common, AR point mutations, and AR overexpression. In addition, restoration of downstream signaling through alternate pathways can also lead to androgen-independent growth of PCa. Therapeutic strategies to overcome these resistance mechanisms and establish predictive biomarkers are still in clinical trials. This review article details the current evidence on clinically relevant driver mechanisms, relevant biomarkers, and treatment modalities to overcome resistance. Abstract Understanding of the molecular mechanisms of prostate cancer has led to development of therapeutic strategies targeting androgen receptor (AR). These androgen-receptor signaling inhibitors (ARSI) include androgen synthesis inhibitor-abiraterone and androgen receptor antagonists-enzalutamide, apalutamide, and darolutamide. Although these medications provide significant improvement in survival among men with prostate cancer, drug resistance develops in nearly all patients with time. This could be through androgen-dependent or androgen-independent mechanisms. Even weaker signals and non-canonical steroid ligands can activate AR in the presence of truncated AR-splice variants, AR overexpression, or activating mutations in AR. AR splice variant, AR-V7 is the most studied among these and is not targeted by available ARSIs. Non-androgen receptor dependent resistance mechanisms are mediated by activation of an alternative signaling pathway when AR is inhibited. DNA repair pathway, PI3K/AKT/mTOR pathway, BRAF-MAPK and Wnt signaling pathway and activation by glucocorticoid receptors can restore downstream signaling in prostate cancer by alternative proteins. Multiple clinical trials are underway exploring therapeutic strategies to overcome these resistance mechanisms.

[9] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

Authors: W. Tulalamba, T. Janvilisri
Year: 2012
Venue: International Journal of Cell Biology
URL: https://www.semanticscholar.org/paper/307cb9186444d9dad6e2e3b53763be0de76de186
DOI: 10.1155/2012/594681
PMID: 22500174
PMCID: 3303613
Citations: 93
Influential citations: 5
Summary: The molecular signaling pathways in the NPC are discussed for the holistic view of NPC development and progression and the important insights toward NPC pathogenesis may offer strategies for identification of novel biomarkers for diagnosis and prognosis.
Evidence snippets:
Snippet 1 (score: 0.436) > In the pregenomic eras, highly integrated and complex circuitry of molecular signaling in NPC pathogenesis was only partially understood. Over the past decade, the knowledge of the molecular mechanisms in NPC carcinogenesis has been rapidly accumulated. Dysregulation and abnormal protein expression of molecules in certain signaling pathways involved in cellular functions including proliferation, adhesion, survival, and apoptosis has been demonstrated in the NPC cells. Detailed information on the complex network in signaling pathway leading to a coordinated pattern of gene expression and regulation in NPC will undoubtedly provide important clues to develop novel prognostic and therapeutic strategies for this cancer. Refining molecular markers into clinically relevant assays may assist in the detection of NPC in asymptomatic patients, as well as stage classification and monitoring disease progression and treatments. Furthermore, selective regulation of particular proteins targeting cancer cell proliferation, invasion, and apoptosis is a hopeful prospect for future anticancer therapy that slow disease progression and improve survival.

[10] Anti-Proliferative Effect and Induction of Apoptosis in Androgen-Independent Human Prostate Cancer Cells by 1,5-Bis(2-hydroxyphenyl)-1,4-pentadiene-3-one

Authors: Kamini Citalingam, F. Abas, N. Lajis, Iekhsan Othman, R. Naidu
Year: 2015
Venue: Molecules
URL: https://www.semanticscholar.org/paper/1b9c5630e11eb31d7ddfa705fae8ceaa19d66408
DOI: 10.3390/molecules20023406
PMID: 25690296
PMCID: 6272399
Citations: 27
Influential citations: 1
Summary: In conclusion, MS17 demonstrated anti-proliferative effect and induces apoptosis in a time and dose-dependent manner suggesting its potential for development as an anti-cancer agent for androgen-independent prostate cancer.
Evidence snippets:
Snippet 1 (score: 0.430) > Prostate cancer is one of the most commonly diagnosed cancers and a leading cause of cancer death in men. Prostate cancer is a clinically heterogeneous disease which harbors multiple genetic abnormalities accumulated during the progression of the disease. The cellular mechanisms contributing to prostate cancer involve a multistep process that includes the inactivation of tumor suppressor genes and the dysregulation of several oncogenic pathways. Although the exact causes of prostate cancer remain unclear, it has been well documented that androgens (testosterone and 5α-dihydrotestosterone, DHT) play an important role in the physiological development of the normal prostate and prostate cancer [1]. Exposure to higher levels of androgens or overexpression/mutation of androgen receptor often leads to rapid proliferation of prostate cancer cells and, almost all the patients eventually relapse with tumors that become androgen-independent [2,3]. At this stage, the cancer cells begin to metastasize to various organs, ultimately causing the death of the patient. > At the initial stage prostate tumors respond to hormonal therapies, and currently available chemotherapeutic drugs are successful in treating these localized, androgen-dependent cancer. These tumors eventually progress to androgen-independent forms that are refractory to these therapies and treatment thus remains hindered and represents a challenge for the clinical oncologist [4]. This has led to little overall improvement of morbidity and mortality, and therefore novel drugs are required to treat hormone-resistant prostate cancer. Alterations of several molecular pathways are required for the development of androgen independence and the dilemma is how to develop the most effective therapeutic drugs that are required to treat hormone-resistant prostate cancer. Tumor cells activate multiple pathways to survive under castration levels of androgens [5][6][7]. > Curcumin (diferuloylmethane), an active yellow pigment, is a major active component of turmeric. It is isolated from the rhizomes of Curcuma longa and has been widely used for decades in the Asian countries, particularly in South Asia.

[11] The Potential of Metabolomics in Biomedical Applications

Authors: V. González-Covarrubias, E. Martínez-Martínez, L. del Bosque-Plata
Year: 2022
Venue: Metabolites
URL: https://www.semanticscholar.org/paper/abed08d7a691cf6b996b465706dc62a5591731ec
DOI: 10.3390/metabo12020194
PMID: 35208267
PMCID: 8880031
Citations: 163
Influential citations: 5
Summary: This review focuses on the metabolomics that can be applied to improve human health, as well as its trends and impacts in metabolic and neurodegenerative diseases, cancer, longevity, the exposome, liquid biopsy development, and pharmacometabolomics.
Evidence snippets:
Snippet 1 (score: 0.428) > The detected metabolic differences between ERG-positive and ERG-negative prostate cancer demonstrate that the increment in β-oxidation and purine metabolism regularly described for prostate cancer could be principally attributed to TMPRSS2-ERG-negative (transmembrane serine protease 2 (TMPRSS2)) tumors. These results agree with the view that ERG-positive (ETS-Related Gene (ERG)) and ERG-negative prostate tumors should be considered partly different diseases, which may require different treatment strategies. > MacKinnon et al. described the metabolites involved in an androgen-dependent prostate cancer cell line [125]. Methyltrienolone (an androgen receptor agonist) treatment resulted in a metabolic signature characteristic of aggressive prostate cancer. Specifically, researchers observed a decrease in myoinositol, altered glutathione levels, a perturbation of amino-acid levels, a decreased level of methionine, a high level of phosphocholine (PC), and an increase in the phosphocholine/glycerophosphocholine ratio. These metabolites may be useful for monitoring cancer development and aggressiveness [125]. > The in vivo detection of clinically relevant prostate cancer can be improved using metabolomics-derived markers related to Gleason score with non-invasive methods, as is the case for magnetic resonance imaging or positron emission tomography imaging. Analogues of PC, glutamate, and glucose, as identified here, are already applied in prostate cancer studies and have been approved by the U.S. Food and Drug Administration (FDA) for the positron emission tomography imaging of recurrent prostate cancer. The researchers discovered two additional metabolites associated with prostate cancer: hypoxanthine and arginine. Both are associated with prostate cancer recurrence and progression [57]. (see Table 1). > Although it is used less frequently than the other omics approaches, metabolomics has the potential to significantly affect core areas of oncology, including screening, diagnosis, and therapy. However, such applications require a better understanding of how these measurements are connected to human physiology and cancer biology.

[12] Genome-wide differential gene network analysis R software and its application In LnCap prostate cancer

Authors: Gökmen Altay, D. Neal
Year: 2017
Venue: bioRxiv
URL: https://www.semanticscholar.org/paper/8ceb36aeccf2c5e6835634e22aa7391bd1e4c4d5
DOI: 10.1101/129742
Summary: An R software package for condition-specific gene regulatory network analysis based on DC3NET algorithm is introduced and how to derive condition-specific gene targets from expression datasets on genome-wide level using differential gene network analysis is demonstrated.
Evidence snippets:
Snippet 1 (score: 0.426) > Prostate cancer is the second most common cancer in the male population, with an estimated 417,000 new cases diagnosed each year in Europe (Ferlay, 2013).The activation of androgen receptor (AR) through androgens plays a crucial role in the development and progression of prostate cancer (Kaur, 2016;Anantharaman, 2015;Choudhary, 2011;Massie, 2011).For early detection of prostate cancer, prostate specific antigen (PSA) screening method has been used widely as a diagnostic tool (Karatas, 2015).However, PSA fails to discriminate indolent disease which results in over-diagnosis and this may lead to poor prognosis (Abou-Ouf, 2015;Ma, 2015;Myers, 2015).Furthermore, there is no evidence showing that the PSA screening reduces the incidence of death and the underlying mechanism of prostate cancer progression remains largely unknown (Cannistraci, 2014 ;Ren, 2015). > Nowadays, the identification of novel oncogenes or tumor suppressor genes has become popular in tumorigenesis studies in understanding molecular mechanisms that drive disease progression (Ren, 2015).Understanding the working mechanism of molecules in normal cell physiology and pathogenesis allows subtle drug development and helps treatment of a disease, such as cancer (Altay, 2010;Rual, 2005;Schadt, 2009).The advent of systems and network biology enable us to capture interactions occurring within a cell, which can be represented as gene networks.Computational analysis of the networks provides key insights into biological pathways and cellular organization (Altay, 2011). > The biological processes at the gene level are very complex structures as genes dynamically interact with each other.The interactions of these molecules have been changing significantly over time and in different cell conditions such as from normal to cancer (Emmert-Streib, 2012;Califano, 2011).A single gene can participate in different biological processes and regulate different genes at different times.However, diseases are usually consequences of interactions between multiple molecular processes, rather than an abnormality in a single gene (Menche, 2015). > Gene regulatory networks hold the potential to identify specific subnetworks that are dysfunctional in the disease state of a cell.

[13] Altered amino and fatty acids metabolism in Sudanese prostate cancer patients: insights from metabolic analysis

Authors: Dalia Ahmed, E. Abdel-Shafy, Elsadig Ahmed Adam Mohammed, Husam Elden Alnour Bakhet Alnour, Amar Mohamed Ismail et al.
Year: 2024
Venue: Journal of Circulating Biomarkers
URL: https://www.semanticscholar.org/paper/9078ef15ce82d6a27fa0fdeca6e6744d0364336f
DOI: 10.33393/jcb.2024.3146
PMID: 39697480
PMCID: 11653783
Citations: 2
Summary: High levels of fatty acids, phospholipids, cholesterol, valine, leucine, and isoleucine associated with non-hypertensive patients were revealed, and hypertensive patients were associated with high GlycA and GlycB levels and altered amino acid metabolism.
Evidence snippets:
Snippet 1 (score: 0.423) > Prostate cancer (PCa) poses a significant global health challenge, characterized by its increasing incidence and investigation of altered metabolic pathways involving lipids, fatty acids, and free amino acids holds immense importance in understanding the molecular mechanisms driving PCa pathogenesis (10,11). > Among the plethora of molecular factors implicated in PCa pathogenesis, lipids have emerged as pivotal players, governing diverse cellular processes crucial for tumor progression (12). Emerging evidence suggests a complex interplay between lipid metabolism, HTN, and androgen deprivation therapies (ADTs) in PCa patients, adding further layers of complexity to patient care (13,14). Dysregulated lipid metabolism not only fuels the energy demands of proliferating cancer cells but also contributes to the structural integrity of cellular membranes and facilitates signaling pathways crucial for PCa progression (15). Fatty acids, the building blocks of complex lipids, are intricately involved in various cellular processes, including energy production, membrane synthesis, and signaling modulation (16). Perturbations in fatty acid metabolism have been implicated in PCa pathophysiology, influencing tumor aggressiveness, therapeutic resistance, and disease prognosis (17). Metabolomic studies have unveiled alterations in fatty acid composition and metabolism associated with PCa, highlighting their potential as biomarkers for disease diagnosis and therapeutic targets for intervention (10,18). Moreover, free amino acids play pivotal roles in cellular metabolism, serving as precursors for protein synthesis, energy production, and signaling molecules (19). Alteration in amino acid metabolism has been implicated in PCa progression, influencing cell proliferation, invasion, and metastasis (20,21). Metabolomic profiling has uncovered variations in amino acid levels and metabolism in PCa, offering insights into the relation between metabolic rewiring and oncogenic signaling pathways (8,11). > Most metabolomic PCa studies are conducted predominantly in European and Asian populations. The generalization of findings to other ethnic groups may be limited due to inherent genetic, environmental, and lifestyle differences (22). Therefore, investigating altered metabolic pathways in diverse populations, including those from African regions like Sudan, is crucial for elucidating population-specific variations in PCa biology.

[14] Mitochondrial oncobioenergetics of prostate tumorigenesis

Authors: P. Vayalil
Year: 2019
Venue: Oncology Letters
URL: https://www.semanticscholar.org/paper/adecfdca7304673545f754879e9b84e22e0d076a
DOI: 10.3892/ol.2019.10785
PMID: 31611945
PMCID: 6781517
Citations: 12
Influential citations: 1
Summary: Since PC is a slow growing tumor, modulating the MOB profile at specific stages of tumor development may be a novel approach to treat or prevent PC.
Evidence snippets:
Snippet 1 (score: 0.422) > Prostate cancer (PC) is a disease of the old age (1). The specific underlying mechanisms of prostate carcinogenesis have not been unraveled yet. The only well-established risk factors for PC are older age, black race/ethnicity, and a family history of the disease (2,3). Therefore, future progress in combating PC will be highly dependent upon an understanding of the mechanisms involved in the development and steady progression into prostate malignancy. > Mitochondria are emerging as key players in the tumorigenic process of cells by maintaining the biosynthetic and energetic capabilities of cancer cells. Besides compartmentalizing different metabolic pathways, the mitochondria is engaged in the generation of much of the cellular energy, regulation of the redox state of the cell, generation of reactive oxygen species (ROS), buffering Ca 2+ and initiating apoptosis (4). Mitochondria are involved in the final stage of the cellular catabolism and maintain the redox homeostasis at different levels. Through several enzymatic reactions, carbohydrates, fats and proteins are degraded into smaller molecules, which is further converted to pyruvate by glycolysis, fatty acids and amino acids (Fig. 1). Mitochondria further transform these small molecules into NADH and FADH 2 (reduced energy equivalents), through β-oxidation and TCA cycle or rerouted to biosynthetic pathways. The reduced energy equivalents are then utilized by the mitochondrial electron transport chain (ETC) through oxidative phosphorylation (OXPHOS). The electrons liberated by the oxidation of NADH and FADH 2 are passed along a series of carriers of ETC located in mitochondrial inner membrane. The electrons are ultimately transferred to molecular oxygen to form water (Fig. 2). ETC consists of four enzyme complexes (complexes I-IV), and two electron carriers (coenzyme Q and cytochrome c). These complexes are composed of numerous protein subunits encoded by nuclear and mitochondrial genes, except complex II, which are encoded by nuclear genes only.

[15] Identification of key pathways and genes in PTEN mutation prostate cancer by bioinformatics analysis

Authors: Jian Sun, Shugen Li, Fei Wang, Caibin Fan, Jianqing Wang
Year: 2019
Venue: BMC Medical Genetics
URL: https://www.semanticscholar.org/paper/a23ddabb812d435439d6a7a35b3d777e8f445d1f
DOI: 10.1186/s12881-019-0923-7
PMID: 31791268
PMCID: 6889628
Citations: 55
Influential citations: 1
Summary: It is suggested that PTEN mutation in prostate cancer may induce changes in a variety of genes and pathways and affect disease progression, suggesting the significance of PTen mutation in individualized treatment of prostate cancer.
Evidence snippets:
Snippet 1 (score: 0.421) > PTEN, which is a tumor suppressor protein and is very commonly lost across cancer types [19]. The major function of PTEN depends on its phosphatase activity. PTEN mainly inhibits PI3K/AKT pathway activity, while other studies also suggest that PTEN may function through AKT-independent [8]. Mutations in PTEN result in losing its phosphatase activity, which contribute to the Here in our study, we analyzed the gene expression data of prostate cancer obtained from TCGA to uncover the critical pathways and top hub genes associated with PTEN mutation. We found 22% patients with PTEN mutation among all cases. The mRNA expression and clinical affair analyses showed lower expression level of PTEN, higher Gleason score and poorer prognosis in patients with PTEN mutation, which indicated the significance of PTEN mutation in prostate cancer: PTEN mutation correlated with advanced disease and worse outcome. PTEN deletion, transcriptional and epigenetic modifications of PTEN are known mechanisms that could cause deregulation of PTEN [20,21]. Lower PTEN expression level often correlates to disease progression in various cancer types [22][23][24], which makes it one of the important potential mechanisms how PTEN mutation exert the role in disease progression. In the following research, the relationship between PTEN mutation and more details of clinical affairs of prostate cancer requires larger sample data for more accurate results. Now that PTEN mutation contributes to prostate cancer progression, the mechanisms underlying other than PTEN downregulation are critical. GSEA analysis suggests that PTEN mutation were mainly associated with the cell metabolism, proliferation and cancer related pathways. In the cellular processes above, metabolic processes, including glycolysis and lipid metabolism, always play critical roles in cancer progression. Previous studies have shown that the formation of cancer cells requires adaptations across various metabolic processes to satisfy the energy required for their increased rate of proliferation. Dysregulation of lipid metabolism, including upregulation of several lipogenic enzymes, has been a hallmark of prostate cancer, and metabolic target has been shown to be a potential treatment target in prostate cancer [25,26]. Our results indicated that drugs targeting lipid metabolic pathways could contribute to the development of new therapeutic modalities in PTEN mutation prostate cancer

[16] Melatonin and Prostate Cancer: Anti-tumor Roles and Therapeutic Application

Authors: Mark F. Megerian, Jae Seok Kim, Jad Badreddine, Sung Hwi Hong, L. Ponsky et al.
Year: 2023
Venue: Aging and Disease
URL: https://www.semanticscholar.org/paper/15af79038c0432b8f59fa955221bcbb8dc202331
DOI: 10.14336/AD.2022.1010
PMID: 37191417
PMCID: 10187692
Citations: 15
Summary: The currently known mechanisms of melatonin-mediated oncostasis in prostate cancer are described, including those that relate to the indolamine’s ability to modulate metabolic activity, cell cycle progression and proliferation, androgen signaling, angiogenesis, metastasis, immunity and oxidative cell status, apoptosis, genomic stability, neuroendocrine differentiation, and the circadian rhythm.
Evidence snippets:
Snippet 1 (score: 0.419) > One of the many ways by which tumor cells alter their metabolic activity to sustain survival is to increase the uptake and utilization of glucose. The Warburg Effect describes the reliance of tumor cells on anaerobic respiration through the glycolytic pathway rather than mitochondrial aerobic respiration, even in the presence of oxygen [33]. For this reason, Otto Warburg dubbed this seemingly paradoxical phenomenon aerobic glycolysis in the 1920s [34], and since then, extensive research has elucidated numerous mechanisms of increased glucose uptake and utilization that support this unique metabolic phenotype in tumor cells [35]. In prostate cancer, glucose metabolism is involved in the progression of carcinogenesis [36], where oxidative phosphorylation is active early in disease progression [37], and the Warburg effect takes over in later stages of the disease [38]. The role of melatonin in glucose bioenergetics of prostate cancer has been studied. After previously demonstrating that the major mechanism of melatonin uptake in LNCaP and PC-3 prostate cancer cells were mediated via an active process rather than passive diffusion [39], Hevia et al. later demonstrated a melatonin receptor-independent mechanism of melatonin uptake through members of the glucose transporter (GLUT) family transporters. Specifically, indolamine was found to interact at the same location as GLUT1 and prevented glucose uptake after 30 min, 1, 3, and 6 hours. Intracellular melatonin concentration was diminished as well with the administration of glucose and other known GLUT1 competitive ligands, suggesting competition between melatonin and glucose by the glucose transporter. This competition was then demonstrated in vivo where pharmacological doses of melatonin attenuated the glucose-induced tumor progression and prolonged transgenic adenocarcinoma of the mouse prostate (TRAMP) mice survival [40]. > The same research team further examined the specific roles of melatonin in prostate cancer metabolism. Utilizing 13C-labeled metabolites and measuring adenosine triphosphate (ATP)/adenosine monophosphate (AMP) levels and lactate dehydrogenase and pentose phosphate pathway activity, Hevia et al. discovered numerous melatonin-induced metabolic

[17] Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer

Authors: O. Bamodu, Kai-Yi Tzou, Chia-Da Lin, Su-Wei Hu, Yuan-Hung Wang et al.
Year: 2021
Venue: Cancers
URL: https://www.semanticscholar.org/paper/e0c4d3081fa727779e464de749f88d0b405d1fd5
DOI: 10.3390/cancers13143478
PMID: 34298692
PMCID: 8303483
Citations: 8
Summary: The findings highlight the role and exploitability of testosterone metabolic reprogramming in prostate TME for patient stratification and personalized/precision medicine based on the differential but concerted expression of molecular components of the proposed testosterone tetrad in patients with therapy-refractory, locally advanced, or recurrent PCa.
Evidence snippets:
Snippet 1 (score: 0.417) > Predicting therapy response and/or clinical outcome in patients with newly diagnosed PCa is challenging. This is in part because of the current non-standardized imaging methods for assessing disease dissemination and the confounding dynamism of the most frequently altered PCa-associated biomarker, prostate-specific antigen (PSA), which makes the latter a less reliable or accurate surrogate biomarker of disease course or treatment response. For instance, about 20% of patients with CRPC who later respond to chemotherapy would have been tagged "non-responders" because of an initial persistent rise in PSA level, which did not decline until after week 12 of chemotherapy or did not decline at all when on immune checkpoint blockade therapy [10]. This modest or non-association between changes in post-treatment PSA level and therapy response or disease recurrence highlights a critical unmet need in PCa management-the need for more reliable and accurate indicators of patient status, namely therapy response or disease recurrence. > Advances in tumor biology increasingly highlight the genomic complexity of cancerous cells, irrespective of tissue origin or histological sub-type [11]. However, within this broad genomic/genetic landscape, some cancer types are more dependent on certain oncogenic pathways for survival than others. This state of preferential "oncogene addiction" is common with aberrant oncometabolic activity, and provides therapeutic basis for molecular targeting of dysregulated oncogenic metabolites [11]. The apparent dependence of cancerous prostate cells on androgen/testosterone metabolic signaling for their survival and the maintenance of their malignant therapy-resistant and recurrent phenotypes makes molecular components of testosterone metabolic reprogramming exploitable for reliably accurate prediction of disease course, therapy response, and clinical outcome, thus, aiding patient stratification and informing therapeutic decision-making when managing patients just diagnosed with PCa. > The present study harnesses the profiling of disease-relevant molecular players, namely testosterone metabolites, HSD17B2, HSD17B3, SHBG, and SRD5A1 to provide an evidence-based platform for exploring and identifying biomarkers that may inform patient stratification, allow prediction of treatment efficacy, and determine mechanism(s) of drug resistance

[18] AMPed up to treat prostate cancer: novel AMPK activators emerge for cancer therapy

Authors: M. Schiewer, K. Knudsen
Year: 2014
Venue: EMBO Molecular Medicine
URL: https://www.semanticscholar.org/paper/92b6a0d8b95812d9b2d4f54129102bc67937fc14
DOI: 10.1002/emmm.201303737
PMID: 24562461
PMCID: 3992071
Citations: 5
Summary: A new study by Zadra et al identifies the energy sensor AMPK (5′ AMP‐activated kinase) as a viable therapeutic target in prostate cancer.
Evidence snippets:
Snippet 1 (score: 0.417) > D espite recent advances in the treatment for metastatic prostatic adenocarcinoma (MacVicar & Hussain, 2013), clinical management of this tumor type remains a major challenge, and there is as of yet no durable cure for advanced disease. Prostate cancer generally responds poorly to standard chemotherapy, but is heavily dependent on signaling of the androgen receptor (AR) for growth and survival (Knudsen & Penning, 2010). Thus, the mainstay of treatment targets this dependence, combining mechanisms to either deplete the AR of ligand or through the use of direct AR antagonists. Although these strategies are initially effective, recurrent tumors deemed "castrate-resistant prostate cancer" (CRPC) ultimately arise. Developing pathways that could be co-targeted alongside AR or that would otherwise thwart the development of the CRPC is a current translational and clinical priority. > In this issue, a new study by Zadra et al (2014) identifies the energy sensor AMPK (5′AMP-activated kinase) as a viable therapeutic target in prostate cancer. AMPK is a serine/threonine kinase that functions as a metabolic sensor that is sensitive to AMP/ ATP levels and serves to enhance ATP generation (Hardie, 2011). In mammalian cells, the kinase exists as a heterotrimer comprised of a single a (catalytic) subunit in addition to two ß and c regulatory subunits as such, variant AMPK complexes exist and may be divergent dependent on cellular context. In spite of this complexity, common activation events occur when the  subunit is phosphorylated on threonine 172, which occurs in the T-loop (Carling et al, 2012 The cellular function of AMPK is to respond to metabolic state and oncogenic stress. Activated AMPK induces catabolic metabolism and suppresses the anabolic state, thereby inhibiting cellular proliferation and potentially serving a tumor suppressive role (Liang & Mills, 2013). Consistent with this idea, AMPK loss can promote tumor progression, as genetic deletion of the AMPK a1 subunit potentiated Myc-induced lymphomagenesis (Faubert et al, 2013). At the molecular level, the tumor suppressive role of activated AMPK is associated with inhibition of cell cycle progression, cholesterol and fatty acid

[19] Characterization of the Biochemical Recurrence Prediction Ability and Progression Correlation of Peroxiredoxins Family in Prostate Cancer Based on Integrating Single‐Cell RNA‐Seq and Bulk RNA‐Seq Cohorts

Authors: Shan Tang, Jinchuang Li, W. Tian, Yuanfa Feng, Yu-Chiao Deng et al.
Year: 2025
Venue: Cancer Medicine
URL: https://www.semanticscholar.org/paper/4ce2d7c8df3aa94185cbd786253fec27032e2998
DOI: 10.1002/cam4.70855
PMID: 40281661
PMCID: 12031674
Citations: 1
Influential citations: 1
Summary: The peroxiredoxins (PRDXs) family plays a crucial role in balancing reactive oxygen species (ROS) levels in tumor cells. However, its potential role in prognosis and therapy response of prostate cancer (PCa) remains unknown.
Evidence snippets:
Snippet 1 (score: 0.416) > Prostate cancer (PCa) is one of the most prevalent cancers in the world, with 299,010 new cases in the United States in 2024 and 1,466,680 new cases globally in 2022 [1,2]. Most PCa is indolent at the time of diagnosis. Biochemical recurrence (BCR) is a critical stage in the progression of PCa [3]. Approximately 35% of patients experience BCR after receiving radical prostatectomy (RP) or radiation therapy (RT), with elevated prostate-specific antigen (PSA) levels commonly used as a reference in clinical practice [4]. Once PCa progresses to a more advanced stage, it advances rapidly and significantly increases the mortality rate of patients [5]. Without proper treatment, about 40% of patients will experience prostate cancer-specific death within 15 years [6]. Drug resistance is a major cause of treatment failure in PCa. Thus, clinicians must assess whether patients require personalized therapy. Exploring a reliable criteria to identify high-risk patients and the underlying mechanisms of BCR are urgently needed. > Reactive oxygen species (ROS), a wide set of unstable oxygencontaining molecules, are typical by-products of cellular metabolism and serve as signaling agents, impacting a range of cellular processes [7]. An alteration in the equilibrium of redox homeostasis, whether due to excessive or inadequate generation of ROS, can have detrimental effects and is associated with several clinical diseases [8,9]. Elevated ROS levels can inhibit tumor cell growth by inducing oxidative DNA damage, enhancing cell cycle arrest, and promoting apoptosis [10][11][12]. The capacity to manage ROS from mitochondrial oxidative metabolism determines the proliferative outcome of cancer cells [13]. In addition, commonly used chemotherapeutic medications exhibit anti-tumor actions, partially by inducing high levels of ROS [14]. The capacity of cancer cells to adapt to inherent or drug-induced oxidative stress plays a role in their resistance to chemotherapy and ultimately contributes to the progression of the disease [15,16].

[20] Hormonal therapy and chemotherapy in hormone-naive and castration resistant prostate cancer

Authors: F. Recine, C. Sternberg
Year: 2015
Venue: Translational Andrology and Urology
URL: https://www.semanticscholar.org/paper/414cf853b7e613b33701d3034cf69d3e53929cad
DOI: 10.3978/j.issn.2223-4683.2015.04.11
PMID: 26816835
PMCID: 4708230
Citations: 24
Influential citations: 2
Summary: The management of advanced castration resistant prostate cancer (CRPC) has been rapidly changing and is still evolving.
Evidence snippets:
Snippet 1 (score: 0.415) > Even though the AR plays a major role in the progression to CRPC, alternative pathways can have a role in stimulating prostate cancer cells, confirming the cellular heterogeneity in prostate cancer (39,40). > Prostate cancer cells can develop alternative AR independent molecular pathways for survival that bypass AR activation, including cancer stem cells, receptor tyrosine kinases and neuroendocrine differentiation (NE) (41). A potential mechanism for survival in the castrate environment is the presence of prostate cancer stem cells that continually supply the cancer cell population, despite therapy. These cells are not affected by ADT and can differentiate into androgen dependent and independent cells, leading to a heterogeneous phenotype of AR (42,43). > Activation of the PI3 kinase signaling pathway is critical for the survival of prostate cancer cells. PTEN is a tumor suppressor and has lipid phosphatase activity that metabolizes PIP3 (phosphatidylinositol triphosphate). The PTEN function is expressed primarily through negative regulation of the PI3K/Akt pathway. PTEN is inactivated in several types of cancers, including prostate cancer. Loss of PTEN function in prostate cancer can occur through several mechanisms, including deletion, mutation and methylation. These events can cause tumor cell survival through selective pressure caused by ADT (44)(45)(46). > Another potentially relevant pathway is NE of tumor cells in prostate cancer. The prevalence of NE cells in prostate adenocarcinoma varies from 30% to 100% and they do not express the AR. These cells may develop from a predominantly adenocarcinoma PSA secreting environment under the pressure of ADT. NE cells may contribute to the progression to CRPC through the production of neurosecretory products, such as parathyroid hormone-related protein, the neurotransmitter serotonin, the neuropeptide hormone bombesin, calcitonin, chromagranin A, neurotensin, and thyroid-stimulatory hormone (6,44,45). Patient with predominantly NE or small cell carcinoma should be treated with cisplatin based chemotherapy (47).

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[1] Inflammatory Microenvironment in Prostate Carcinogenesis

[2] РАК ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ, СОВРЕМЕННЫЕ ТЕРАПЕВТИЧЕСКИЕ ПОДХОДЫ И ВОЗМОЖНЫЕ ПЕРСПЕКТИВЫ

[3] PANCREATIC CANCER, CURRENT THERAPEUTIC APPROACHES AND POSSIBLE PROSPECTS

[4] Immunotherapy in prostate cancer: new horizon of hurdles and hopes

[5] Castration-Resistant Prostate Cancer: Targeted Therapies and Individualized Treatment

[6] Fatty Acid Synthesis in Prostate Cancer: Vulnerability or Epiphenomenon?

[7] Signalling pathways in a nutshell: from pathogenesis to therapeutical implications in prostate cancer

[8] Androgen Receptor Signaling in Prostate Cancer and Therapeutic Strategies

[9] Nasopharyngeal Carcinoma Signaling Pathway: An Update on Molecular Biomarkers

[10] Anti-Proliferative Effect and Induction of Apoptosis in Androgen-Independent Human Prostate Cancer Cells by 1,5-Bis(2-hydroxyphenyl)-1,4-pentadiene-3-one

[11] The Potential of Metabolomics in Biomedical Applications

[12] Genome-wide differential gene network analysis R software and its application In LnCap prostate cancer

[13] Altered amino and fatty acids metabolism in Sudanese prostate cancer patients: insights from metabolic analysis

[14] Mitochondrial oncobioenergetics of prostate tumorigenesis

[15] Identification of key pathways and genes in PTEN mutation prostate cancer by bioinformatics analysis

[16] Melatonin and Prostate Cancer: Anti-tumor Roles and Therapeutic Application

[17] Differential but Concerted Expression of HSD17B2, HSD17B3, SHBG and SRD5A1 Testosterone Tetrad Modulate Therapy Response and Susceptibility to Disease Relapse in Patients with Prostate Cancer

[18] AMPed up to treat prostate cancer: novel AMPK activators emerge for cancer therapy

[19] Characterization of the Biochemical Recurrence Prediction Ability and Progression Correlation of Peroxiredoxins Family in Prostate Cancer Based on Integrating Single‐Cell RNA‐Seq and Bulk RNA‐Seq Cohorts

[20] Hormonal therapy and chemotherapy in hormone-naive and castration resistant prostate cancer

Notes