Chemical Agonists of the PML/Daxx Pathway for Prostate Cancer Therapy

摘要

Metastatic, hormone refractory prostate cancer is currently an incurable disease. Consequently, novel therapeutic agents are needed that promote killing of malignant prostate cancer cells in a more efficient, less toxic manner. The goal of this project was to identify chemicals that activate an endogenous anti-cancer mechanism that induces tumor cell suicide and auto- destruction. To achieve this goal, we focused on an intrinsic tumor suppressor system involving the proteins PML and Daxx, which control the activity of the genome and render tumor cells more vulnerable to cell death. We devised robotic automated screening methods that permited us to test a collection of chemicals in search of molecules with the proper characteristics to activate the PML/Daxx tumor suppressor pathway in hormone refractory prostate cancer cells. The chemicals identified provide a starting point for futher optimization with respect to their chemical structures so that they are potent and have the proper behavior in the body to reach tumor cells at effective concentrations. Altogether, these efforts provide a foundation for innovative new experimental therapeutics for advanced prostate cancer.