Elicit: What are the most effective molecular targets for treatment of metastatic neuroendocrine prostate cancer in patients who have failed standard androgen deprivation therapy? (public)

What are the most effective molecular targets for treatment of metastatic neuroendocrine prostate cancer in patients who have failed standard androgen deprivation therapy? (public)

Study Design

Participant/Sample Characteristics

Molecular Targets Investigated

Intervention Details

Key Findings and Efficacy

P450-dependent enzymes as targets for prostate cancer therapy
R. Coster, Walter Wouters, J. Bruynseels
Journal of Steroid Biochemistry and Molecular Biology, 1996, 78 citations, DOI

Feasibility of targeted therapy based on immunohistochemical expression analysis in androgen-independent prostate cancer
C. Ohlmann, E. Markert, M. Gerharz, D. Pfister, H. Dienes, and 2 more
Der Urologe (Ausg. A), 2008, 0 citations, DOI

Characteristics

• Type of cancer samples: Metastatic prostate adenocarcinoma
• Number of samples/patients: Insufficient data
• Stage of cancer: Metastatic
• Prior treatment history: Relapse after surgical or medical castration
• Molecular characteristics: Insufficient data

Molecular Targets

• Cytochrome P450-dependent enzymes (17,20-lyase, aromatase)
• Method of Investigation: Inhibitors (ketoconazole, newly synthesized steroidal 17,20-lyase inhibitors), liarozole fumarate (LIA)
• Rationale for Targeting: Achieving maximal androgen ablation, enhancing retinoid-mimetic effects
• Specific Molecular Characteristics: Involvement in steroid and retinoic acid metabolism

Treatment Methods

• Orchidectomy:
  • Mechanism: androgen deprivation
  • Combination: often with LHRH analogues and androgen receptor antagonists
• LHRH analogues:
  • Mechanism: androgen deprivation
  • Combination: often with orchidectomy and androgen receptor antagonists
• Ketoconazole:
  • Specific drug/treatment name: Ketoconazole
  • Mechanism: blocks testicular and adrenal androgen biosynthesis
  • Dosage: high dose
  • Route of administration: not specified
  • Duration of treatment: not specified
• Aminoglutethimide + Hydrocortisone:
  • Specific drug/treatment name: Aminoglutethimide + Hydrocortisone
  • Mechanism: suppresses adrenal androgen biosynthesis
  • Dosage: not specified
  • Route of administration: not specified
  • Duration of treatment: not specified
• Liarozole fumarate (LIA):
  • Specific drug/treatment name: Liarozole fumarate
  • Mechanism: blocks P450-dependent catabolism of retinoic acid
  • Dosage: not specified
  • Route of administration: not specified
  • Duration of treatment: not specified
  • Combination therapies: monotherapy

Key Findings

• Molecular changes: Increased differentiation and changes in cytokeratin patterns.
• Treatment response: LIA induces PSA responses in about 30% of unselected patients.
• Tumor shrinkage: Regression of soft tissue metastasis observed in some patients.
• Survival metrics: Not mentioned.
• Mechanism of action confirmation: LIA blocks P450-dependent catabolism of retinoic acid, enhancing its antiproliferative and differentiation effects.

Molecular characterization study, Clinical trial (phase II)

• Type of cancer samples: Androgen-independent prostate cancer (AIPC)
• Number of samples/patients: 51
• Stage of cancer: Progressive AIPC
• Prior treatment history: 43 (84.3%) had first-line chemotherapy
• Molecular characteristics:
  • EGFR: 61.2%
  • PDGFRbeta: 57.1%
  • Her-2/neu: 16.3%
  • c-KIT: 25.0%
  • VEGF: 74.5%

Molecular Analysis

• EGFR:
  • Method: Immunohistochemical analysis
  • Rationale: Potential role in cancer progression
  • Characteristics: Positive staining in 61.2% of patients
• PDGFRbeta:
  • Method: Immunohistochemical analysis
  • Rationale: Potential role in cancer progression
  • Characteristics: Positive staining in 57.1% of patients
• Her-2/neu:
  • Method: Immunohistochemical analysis
  • Rationale: Potential role in cancer progression
  • Characteristics: Positive staining in 16.3% of patients
• c-KIT:
  • Method: Immunohistochemical analysis
  • Rationale: Potential role in cancer progression
  • Characteristics: Positive staining in 25.0% of patients
• VEGF:
  • Method: Immunohistochemical analysis
  • Rationale: Potential role in cancer progression
  • Characteristics: Positive staining in 74.5% of patients

Treatment Details

• Specific drug/treatment name: Signal transduction inhibitor (STI) and docetaxel
• Mechanism of action: STI inhibits signal transduction pathways; docetaxel inhibits cell division
• Dosage: Not mentioned
• Route of administration: Not mentioned
• Duration of treatment: Not mentioned
• Combination therapies: STI and docetaxel
• Phase of trial: Not specified

Additional Findings

• Molecular changes: Expression of molecular targets found in about 90% of patients with AIPC.
• Specific percentages:
  • EGFR: 61.2%
  • PDGFRbeta: 57.1%
  • Her-2/neu: 16.3%
  • c-KIT: 25.0%
  • VEGF: 74.5%.
• Treatment response: 50% of patients showed a decline in PSA of ≥ 50%.
• Survival metrics: Median survival time was 13.5 months.