## 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.