Development of Molecular Chaperone Inhibitors for Re-Sensitization of CRPC to Enzalutamide and Abiraterone and to Synergize with Metabolic Inhibitors
Abstract
Prostate cancer (PCa) remains the most common non-cutaneous cancer of the American male population and the second leading cause of cancer-related deaths. When diagnosed early, PCa is highly treatable. However, metastatic PCa frequently requires treatment with first-line hormonal ablation therapy and, when resistance to this therapy develops, the patients develop castration-resistant prostate cancer (CRPC), a lethal disease. CRPC patients are frequently treated with second-line, ligand-binding, domain-targeted (LBDT) therapy to antagonize the androgen receptor (AR), the main transcriptional driver in CRPC. While often initially successful in slowing disease progression, CRPC invariably becomes resistant to this therapy. Multiple mechanisms underlie resistance, but two of the more common routes involve mutation/overexpression of full-length AR or truncation of AR to an always-on splice variant (termed Arv). In work supported by a 2015 PCRP Idea Development Award, we uncovered an exciting and unexpectedly central role for the molecular chaperones, Hsp40 and Hsp70, in allowing CRPC cells to become resistant to LBDT therapy. Using large-scale functional genomics, we found that CRPC cells are selectively vulnerable to loss of Hsp40/Hsp70, likely because of their unusual dependence on AR/ARv signaling. Consistent with this idea, chemical inhibition of Hsp40/Hsp70 triggered the rapid, selective, and dramatic loss of AR and ARv proteins in cellular and animal models of CRPC and inhibited tumor growth in animals. Moreover, our recent data show that inhibitors of Hsp40/Hsp70 may restore the sensitivity of CRPC cells to LBDT therapy, while also combining with cancer metabolism inhibitors to even more potently suppress CRPC cell growth. These are exciting findings that could extend the lives of men with metastatic prostate cancer by adding entirely new drugs and drug combinations. In the proposed research plan, we will (1) move Hsp70 and Hsp40 inhibitors closer to clinical testing; (2) probe the mechanisms by which they overcome LBDT therapy resistance in three distinct CRPC cellular models; and (3) learn how they combine with cancer metabolism inhibitors. The proposed studies will improve our understanding of the biology underlying these observations. In addition, they will advance novel inhibitors of Hsp70 and Hsp40 toward becoming safe and effective drugs. Ultimately, our singular goal is to progress these chaperone inhibitors to clinical trials in CRPC patients. The proposed research program is responsive to the goals and mission of the Department of Defense Prostate Cancer Research Program (PCRP) and is specifically responsive to the goal of the PCRP Impact Award, namely to position the program for first-in-human clinical evaluation of one or more of these chaperone inhibitors within 5 years after completion of this Award. The current research proposal addresses the dual 2018 PCRP Overarching Challenges of (1) developing treatments that improve the outcomes for men with lethal prostate cancer and (2) defining the biology of lethal prostate cancer to reduce death.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910716
Entities
People
- Leonard Neckers
Organizations
- National Cancer Institute
- United States Army