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?

Study Design

• Preclinical (in vitro, animal model), Clinical trial

Participant/Sample 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 Investigated

• 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

Intervention Details

• 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 and Efficacy

• 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.

Clinical Insights

Metastatic prostate adenocarcinoma is a leading cause of cancer-related deaths among men. First line treatment is primarily aimed at blocking the synthesis and action of androgens. As primary endocrine treatment, androgen deprivation is usually achieved by orchidectomy or LHRH analogues, frequently combined with androgen receptor antagonists in order to block the residual adrenal androgens. However, nearly all patients will eventually relapse. Available or potential second line therapies include, among others, alternative endocrine manipulations and chemotherapy.

Cytochrome P450-dependent enzymes are involved in the synthesis and/or degradation of many endogenous compounds, such as steroids and retinoic acid. Some of these enzymes represent suitable targets for the treatment of prostate cancer. In first line therapy, inhibitors of the P450-dependent 17,20-lyase may achieve maximal androgen ablation with a single drug treatment. Ketoconazole at high dose limits its widespread use due to side-effects, mainly gastric discomfort.

The role of inhibition of aromatase in prostate cancer therapy has not been confirmed by the use of more selective aromatase inhibitors. An alternative approach is represented by liarozole fumarate (LIA), a compound that blocks the P450-dependent catabolism of retinoic acid (RA). In summary, early clinical trials have shown that through monotherapy with LIA, there could be a notable increase in RA plasma and endogenous tissue levels leading to retinoid-mimetic effects and regression of soft tissue metastasis in some patients.