Precision Targeting in Metastatic Prostate Cancer: Molecular Insights to Therapeutic Frontiers
Abstract
:1. Introduction
2. Molecular Pathophysiology of Metastatic Prostate Cancer
2.1. Centrality of the AR Axis
2.1.1. Historical Underpinnings and Core AR Functions
2.1.2. Routes to AR Reactivation Under Therapeutic Pressure
2.2. PARP Inhibitors and the Synthetic Lethality Paradigm
2.2.1. Historical Context and Foundational Insights
2.2.2. Core Molecular Mechanisms in Prostate Cancer
2.2.3. Adaptive and Resistance Mechanisms
2.2.4. Research Methodologies and Knowledge Gaps
2.2.5. Forward-Looking Perspectives in Molecular Pathophysiology
2.3. TMPRSS2–ERG Fusions and Oncogenic Transcription Factors (Molecular Pathophysiology Focus)
2.3.1. Historical to Current Understanding
2.3.2. Mechanistic Insights
2.3.3. Methodological Limitations
2.3.4. Clinical or Scientific Significance
2.3.5. Comparisons, Divergent Findings, and Future Outlook
2.4. PTEN Loss, PI3K/AKT/mTOR Hyperactivation, and Crosstalk with AR
2.4.1. Historical to Current Perspective
2.4.2. Mechanistic Insights
2.4.3. Methodological Constraints
2.4.4. Clinical or Scientific Significance
2.4.5. Contrasting Evidence and Future Directions
2.5. Tumor Heterogeneity, Clonal Evolution, and Lineage Plasticity
2.5.1. Historical to Current Understanding
2.5.2. Mechanistic Insights into Clonal Dynamics
2.5.3. Methodological Constraints
2.5.4. Clinical or Scientific Significance
2.5.5. Comparisons and Divergent Data
2.5.6. Future Outlook
2.6. The Tumor Microenvironment and Immune Dynamics
2.6.1. Historical to Current Understanding
2.6.2. Mechanistic Insights
2.6.3. Methodological Constraints
2.6.4. Clinical or Scientific Significance
2.6.5. Comparisons and Divergent Data
2.6.6. Future Outlook
TME Component | Key Secreted Factors/Regulatory Signals | Main Function/Immune Evasion Mechanism | Clinical Implications |
---|---|---|---|
TAMs | IL-10, TGF-β, PD-L1 | Suppress cytotoxic T-cell responses, promote angiogenesis and tumor growth | Elevated TAMs infiltration correlates with poor prognosis; potential therapeutic target for immunomodulation |
MDSCs | Arginase, ROS, NO, IL-10 | Inhibit T-cell function and antigen presentation, reinforce immunosuppression | High MDSCs levels linked to rapid disease progression; blocking MDSC recruitment or function may enhance immunotherapy outcomes |
Tregs | IL-10, TGF-β | Suppress effector T-cell activity through cytokine-mediated and cell-contact mechanisms | Increased Tregs infiltration is associated with worse prognosis; Treg depletion or functional blockade may boost response to immunotherapy |
CAFs | TGF-β, FGF, CXCL12, extracellular matrix components | Provide structural support, secrete growth factors that promote tumor invasion, and create immunosuppressive niches | FAP has emerged as a potential target; CAFs remodeling could improve T-cell infiltration in solid tumors |
Bone Metastasis Niche (Osteoblasts/Osteoclasts) | RANKL, OPG, TGF-β | Remodel bone microenvironment to favor tumor cell growth, contribute to immune evasion through altered cytokine milieu | Central to skeletal metastases in prostate cancer; targeted RANKL inhibition (e.g., denosumab) or other bone-directed therapies may impair tumor progression |
Endothelial Cells & Angiogenic Factors | VEGF, FGF, PDGF | Induce neovascularization that sustains tumor growth and metastasis | Anti-angiogenic strategies may enhance immunotherapy by reprogramming the tumor vasculature and improving immune cell infiltration |
3. Molecular Stratification and Diagnostic Advances
3.1. High-Resolution Molecular Profiling
3.2. Companion Diagnostics and Gene Panels
3.2.1. DDR-Focused Panels for PARP Inhibitor Selection
3.2.2. AR Variant Detection and PTEN/PI3K Panels
3.2.3. Performance Metrics of Key Molecular Biomarkers
3.3. Advanced Imaging: PSMA PET-CT and Beyond
3.4. Liquid Biopsies in Metastatic Prostate Cancer
3.4.1. Historical Context and Technological Evolution
3.4.2. Methodological Approaches and Clinical Relevance
3.4.3. Critical Assessment and Significance
3.4.4. Methodological Challenges
3.4.5. Future Outlook
4. Targeted Therapeutic Approaches
4.1. AR Axis–Centric Treatments
4.2. DDR-Defect-Based Therapies: PARP Inhibitors and Beyond
4.3. Targeting PI3K/AKT/mTOR and WNT Pathways
4.4. Immuno-Oncology Approaches
4.5. PSMA-Targeted Radioligand Therapy
5. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
ADT | androgen deprivation therapy |
AR | androgen receptor |
ARE | androgen response element |
CAR-T | chimeric antigen receptor T |
cfDNA | cell-free DNA |
CRISPR | clustered regularly interspaced short palindromic repeats |
CTC | circulating tumor cell |
ctDNA | circulating tumor DNA |
DBD | DNA-binding domain |
DDR | DNA damage repair |
DHT | testosterone–dihydrotestosterone |
DSB | double-strand break |
EMT | epithelial–mesenchymal transition |
FAP | fibroblast activation protein |
HR | homologous recombination |
LBD | ligand-binding domain |
mCRPC | metastatic castration-resistant prostate cancer |
MDSC | myeloid-derived suppressor cell |
mPCa | metastatic prostate cancer |
NGS | next-generation sequencing |
NTD | N-terminal transactivation domain |
PARP | poly-ADP ribose polymerase |
PCa | prostate cancer |
PIP3 | phosphatidylinositol (3,4,5)-trisphosphate |
PROTAC | proteolysis-targeting chimera |
PSA | prostate-specific antigen |
PSMA | prostate-specific membrane antigen |
TAM | tumor-associated macrophage |
t-NEPC | treatment-emergent neuroendocrine prostate cancer/treatment-induced neuroendocrine prostate cancer |
TME | tumor microenvironment |
Treg | regulatory T cell |
WES/WGS | whole-exome/genome sequencing |
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Molecular Target or Genetic Alteration | Key Mechanism/Function | Clinical Features | Clinical Utility |
---|---|---|---|
AR Amplification/AR Splice Variants (e.g., AR-V7) | Sustained AR signaling under low-androgen conditions; ligand-independent activation | Poor response or resistance to AR-targeted therapies; commonly seen in mCRPC | Predicts resistance to enzalutamide or abiraterone; potential biomarker for treatment selection |
PTEN Loss | Hyperactivation of the PI3K/AKT/mTOR pathway; cross-talk with AR signaling | Associated with high-grade tumors and aggressive clinical course | May guide PI3K/AKT/mTOR inhibitor-based combination trials; potential prognostic indicator |
DDR Defects (e.g., BRCA2, ATM) | Impaired DNA repair and increased genomic instability; vulnerability to PARP inhibition | More aggressive behavior if untreated; better response to PARP inhibitors | Companion diagnostics for PARP inhibitors; synthetic lethality-based therapy targeting |
TMPRSS2–ERG Fusion | ETS transcription factor (ERG) overexpression; promotes invasion, EMT, and genomic instability | High prevalence in localized prostate cancer; variable association with outcomes in mPCa | Potential prognostic marker in combination with other alterations (e.g., PTEN) |
PI3K/AKT/mTOR Mutations | Aberrant cell proliferation and survival; metabolic reprogramming | Often co-occurs with AR pathway alterations; contributes to therapeutic resistance | Under investigation in clinical trials targeting AKT and mTOR; potential combination strategy with AR inhibitors |
TP53/RB1 Co-mutations | Disruption of cell-cycle checkpoints; may facilitate lineage plasticity or neuroendocrine differentiation | Common in advanced mPCa; associated with poor prognosis | Emerging biomarker for early switch to chemotherapy or combination therapies |
Diagnostic Panel/Biomarker | Testing Method | Clinical Significance | Limitations/Considerations |
---|---|---|---|
DDR-Focused Panel (BRCA1/2, ATM, etc.) | Targeted NGS or expanded gene panels Germline vs. somatic testing | Identifies candidates for PARP inhibitors and platinum-based therapies May inform familial genetic risk | Cost and limited access in some regions May miss epigenetic alterations |
AR Splice Variants (e.g., AR-V7) | RT-PCR or ddPCR on CTCs Tissue-based RNA assays | Predicts resistance to enzalutamide or abiraterone Can guide switch to chemotherapy or other targeted agents | Variable sensitivity depending on assay Not yet universally available or standardized |
PTEN/PI3K/AKT | IHC, FISH Targeted sequencing for hotspot mutation | Potential biomarker for AKT/mTOR inhibitors May correlate with disease aggressiveness | Limited predictive validation in some trials Reimbursement issues in certain regions |
TP53/RB1 | Targeted NGS or WES/WGS IHC for protein loss | Associated with poor prognosis May indicate early progression toward neuroendocrine differentiation | Rarely used in routine practice Data interpretation can be complex (co-occurring events) |
TMPRSS2–ERG Fusion | FISH, RT-PCR, or RNA-seq | Possible prognostic marker when combined with other aberrations (e.g., PTEN) | Prognostic impact remains debated May not be actionable with current therapies |
Biomarker | Common Test Method (s) | Sensitivity (%) | Specificity (%) | PPV (%) | NPV (%) | Notes/References |
---|---|---|---|---|---|---|
AR-V7 (Circulating Tumor Cells) | RT-PCR or ddPCR of isolated CTCs | ~60–80 | ~70–90 | ~65–85 | ~70–90 | Varies by platform and cutoff used. Higher PPV for resistance to AR inhibitors [104,108]. Not standardized across all labs. |
BRCA1/2 & DDR Panel (Genomic Testing) | NGS panels (targeted, WES) | ~85–95 | ~95–99 | ~90–95 | ~85–95 | Typically, high analytical accuracy for well-validated panels [6,89]. Clinical performance depends on presence of true driver mutations. |
PTEN Loss (tissue-based) | IHC or FISH | ~70–80 | ~80–90 | ~60–85 | ~75–90 | Studies show variability in PTEN detection [52]. Co-occurring alterations (e.g., TP53) may influence true clinical impact. |
TP53/RB1 (tissue-based) | Targeted NGS, WES/WGS, IHC for protein | ~70–90 | ~85–95 | ~80 | ~85 | Highly dependent on sample purity and co-mutations [109]; associated with poor prognosis |
Mismatch Repair Defects (e.g., MSH2, MLH1) | IHC for mismatch repair proteins, NGS | ~85–95 | ~85–95 | ~75–90 | ~90 | Predictive for PD-1 checkpoint inhibition; modest incidence in PCa [6] |
TMPRSS2–ERG Fusion (Tissue-Based Assays) | FISH, RT-PCR, or RNA-seq in tumor tissue | ~50–70 | ~80–95 | ~70–90 | ~60–80 | Variable positivity rates in localized vs. metastatic PCa [49,56]. Prognostic value still debated. |
Modality | Specimen Characteristics | Analytical Techniques | Clinical Applications | Advantages | Limitations |
---|---|---|---|---|---|
ctDNA | Cell-free DNA fragments shed by tumor cells Detected in plasma or serum | Targeted/whole-exome NGS ddPCR | Real-time monitoring of tumor burden Detection of actionable mutations (e.g., BRCA2) | Minimally invasive Repeat sampling feasible Reflects genomic heterogeneity | Low abundance in early disease Sensitivity depends on tumor fraction Assay costs and standardization issues |
CTCs | Intact, viable tumor cells in the bloodstream May be enriched via immunomagnetic or size-based separation methods | Immunophenotyping Single-cell genomics/transcriptomics | Prognostic biomarker (CTC count) AR-V7 status for therapy guidance Potential ex vivo drug testing | Allows morphological and molecular analyses Provides insight into specific cell populations | Rare cells, labor-intensive Limited sensitivity in low-volume disease Heterogeneity among different CTC populations |
Exosomes and Extracellular Vesicles | Nano-scale vesicles containing proteins, RNA, and DNA Released by tumor and stromal cells into bodily fluids | RNA-seq, proteomics Nanoparticle tracking Advanced mass spectrometry | May reveal early resistance signatures Potential biomarkers for immune and stromal interactions | Reflects active secretory pathways Can capture tumor–stromal communication | Isolation protocols not standardized Complexity of vesicle subtypes Data interpretation is challenging |
Treatment or Combination | Primary Target/Mechanism | Trial Phase | Patient Population | Key Outcomes | Current Status | Reference |
---|---|---|---|---|---|---|
Olaparib vs. Abiraterone/Enzalutamide (PROfound) | PARP inhibition (DDR deficiency) | Phase III | mCRPC with HRR gene alterations (e.g., BRCA1/2) | Improved radiographic PFS and OS in biomarker-selected patients | Approved for HRR-mutated mCRPC | [175] |
Ipatasertib + Abiraterone (IPATential150) | AKT inhibitor + AR axis blockade | Phase III | mCRPC, particularly with PTEN loss | Prolonged PFS in the PTEN-loss subgroup | Ongoing or completed; subset analyses continuing | [151] |
177Lu-PSMA-617 + Standard of Care (VISION) | PSMA-targeted radioligand therapy | Phase III | Heavily pretreated mCRPC | Improved OS and PFS vs. standard care | Approved in multiple regions | [176] |
Nivolumab + Ipilimumab (CheckMate 650) | Dual immune checkpoint blockade (PD-1, CTLA-4) | Phase II | mCRPC, previously treated | Moderate objective response; significant immune-related toxicity | Further refinement of combination strategies needed | [177] |
Pembrolizumab (KEYNOTE-199) | PD-1 immune checkpoint blockade | Phase II | mCRPC with prior treatments | Modest response rates; better outcomes in MSI-H or DNA repair defects | Investigational in selected biomarker-defined subgroups | [178] |
Apalutamide (SPARTAN) | Next-generation AR antagonist | Phase III | nmCRPC (non-metastatic CRPC) | Significantly improved metastasis-free survival (MFS) | Approved for nmCRPC | [179] |
Therapeutic Strategy | Mechanism of Action | Associated Biomarkers | Advantages | Disadvantages/Limitations | Reference |
---|---|---|---|---|---|
AR-Targeted Therapies (e.g., Abiraterone, Enzalutamide, Apalutamide, Darolutamide) | Second-generation agents block AR function by inhibiting ligand binding (enzalutamide) or androgen biosynthesis (abiraterone) | AR-V7 and other splice variants AR amplification, LBD mutations | Mainstay for mCSPC/mCRPC with proven OS benefits Generally well-tolerated compared to chemotherapy Can be combined with other targeted agents | Inevitable resistance (AR mutations/splice variants) Cross-resistance among agents Limited efficacy in NEPC | [29,136,137,140,141,142,143] |
PARP Inhibitors (e.g., Olaparib, Rucaparib) | Exploit synthetic lethality in tumors with deficient DNA repair (e.g., BRCA2) | BRCA1/2, ATM, PALB2, or other DDR gene alterations | Markedly improved outcomes in BRCA2-mutant mCRPC Potential synergy with AR pathway inhibition or chemo Established companion diagnostics for biomarker-driven selection | Resistance via reversion mutations or upregulation of alternative repair pathways Limited efficacy in non-BRCA/ATM-altered tumors Class-related toxicities (myelosuppression, GI events) High cost and variable global availability | [46,146,147] |
Immunotherapy (Checkpoint Inhibitors, Vaccines, Bispecific T cell Engagers) | Enhances immune-mediated tumor recognition and destruction (e.g., PD-1/PD-L1 or CTLA-4 blockade) BiTEs (e.g., STEAP1-targeting) redirect T cells to tumor cells Vaccines stimulate specific T cell responses | MMR deficiency, MSI-H Emerging markers (e.g., tumor mutation burden, PD-L1 expression, STEAP1 expression) | Durable responses in a subset of patients with high TMB/MSI-H Potential synergy with radiation or targeted therapies Bispecific T cell engagers can be highly potent, bypassing the need for prior T cell priming | Prostate cancer is typically immunologically “cold” Limited responses outside biomarker-selected populations Immune-related adverse events (e.g., colitis, dermatitis) BiTE therapies can cause cytokine release syndrome | [154,155,156,157,158,159] |
PSMA-Targeted Radioligand Therapy (e.g., 177Lu-PSMA-617) | Delivers cytotoxic radiation specifically to PSMA-expressing tumor cells | PSMA PET imaging for target expression | Offers both diagnostic (PSMA PET-CT) and therapeutic potential (“theranostics”) Demonstrated survival advantage in heavily pretreated mCRPC (VISION trial) Can target micro-metastatic disease | Not all PCa lesions overexpress PSMA (e.g., neuroendocrine variants) Salivary gland toxicity and xerostomia, especially with alpha-emitters (225Ac) Requires specialized facilities for radiopharmaceutical handling Cost and limited access in some regions | [161,162,167,169,171] |
PI3K/AKT/mTOR Inhibitors (e.g., Ipatasertib, Capivasertib) | Blocks downstream signaling of PI3K/AKT/mTOR axis, often hyperactivated due to PTEN loss | PTEN status PIK3CA, AKT mutations | Potential synergy with AR blockade May delay disease progression in PTEN-deficient mCRPC Encouraging early-phase trial results in combination regimens | On-target metabolic toxicities (hyperglycemia, rash) Relatively modest single-agent activity Patient selection crucial to avoid unnecessary toxicity | [150,151,152,153] |
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Kwon, W.-A.; Joung, J.Y. Precision Targeting in Metastatic Prostate Cancer: Molecular Insights to Therapeutic Frontiers. Biomolecules 2025, 15, 625. https://doi.org/10.3390/biom15050625
Kwon W-A, Joung JY. Precision Targeting in Metastatic Prostate Cancer: Molecular Insights to Therapeutic Frontiers. Biomolecules. 2025; 15(5):625. https://doi.org/10.3390/biom15050625
Chicago/Turabian StyleKwon, Whi-An, and Jae Young Joung. 2025. "Precision Targeting in Metastatic Prostate Cancer: Molecular Insights to Therapeutic Frontiers" Biomolecules 15, no. 5: 625. https://doi.org/10.3390/biom15050625
APA StyleKwon, W.-A., & Joung, J. Y. (2025). Precision Targeting in Metastatic Prostate Cancer: Molecular Insights to Therapeutic Frontiers. Biomolecules, 15(5), 625. https://doi.org/10.3390/biom15050625