Therapy for Castration-Resistant Prostate Cancer

HSP90 as a Target for Mechanism-Based Therapy for Castration-Resistant Prostate Cancer

Introduction

This project is broadly directed toward establishing a paradigm for the development of targeted, mechanism-based, molecular therapeutics for the treatment of castration resistant prostate cancer. The goal is the basic study and clinical development of the ansamycin antibiotics. Ansamycins are natural products and treatment of cancer cells with the antibiotic results in the degredation of a subset of signaling proteins by inhibiting Hsp90. One such drug we are working on is 17-allylamino-geldanamycin (17-AAG) and its water soluble derivative, 17-DMAG.

We have shown that ansamycins inhibit the growth of prostate cancer xenografts using doses and schedules that are non-toxic to the animals. This project proposes further in vitro and animal studies on the mechanism of action of 17-AAG (an ansamycin) alone as monotherapy, in combination with other drugs, and phase I/II trials based on these preclinical studies.

Specifically, this project aims to:

1. Conduct phase 2 clinical trials of the Hsp90 inhibitors 17-AAG or DMAG.
2. Study the inhibition of androgen receptor (AR) expression with pharmacologic inhibitors of AR function.
3. Develop novel orally available Hsp90 inhibitors which can be administered chronically.
4. Translate these findings into clinical trials. The long-term goal of these studies is the successful clinical development of drugs that induce AR degradation as treatment for patients with advanced prostate cancer.

Project Leaders

• Principle Investigator: Howard I. Scher, M.D.
• Co-Principle Investigator: Neal Rosen, M.D., PhD

Collaborators

• David Solit, MD
• Len Neckers, PhD