Unbiased Phenotype-Based Screen Identifies Therapeutic Agents Selective for Metastatic Prostate Cancer

Area of Science:

• Oncology
• Pharmacology
• Drug Discovery

Background:

• Prostate cancer is a leading cause of cancer death in American men.
• Metastatic prostate cancer lacks effective curative treatments.
• Identifying drugs targeting metastatic cells over normal cells is crucial.

Purpose of the Study:

• To screen compounds for selective toxicity against metastatic prostate cancer cells.
• To evaluate promising drug candidates in preclinical models.
• To explore novel therapeutic strategies for advanced prostate cancer.

Main Methods:

• Phenotype-based in vitro drug screening of 1,120 compounds.
• In vivo evaluation in mouse xenograft models (subcutaneous, lung, bone metastasis).
• Formulation of lead compounds as micelles or nanoparticles to improve bioavailability.

Main Results:

• Fenbendazole, fluspirilene, clofazimine, niclosamide, and suloctidil demonstrated preferential cytotoxicity.
• Albendazole and fenbendazole, when formulated, significantly prolonged survival in metastatic mouse models.
• Albendazole outperformed paclitaxel in extending median survival and targeted taxane-resistant tumors and bone metastases.

Conclusions:

• Metastatic prostate tumor cells exhibit differential drug sensitivity compared to benign cells.
• Albendazole shows potential as an adjuvant or neoadjuvant therapy for disseminated prostate cancer.
• Repurposed drugs like albendazole offer a promising avenue for treating aggressive prostate cancer.