Targeting the HSP40/HSP70 Molecular Chaperone Axis as a Novel Treatment Strategy for Castrate-Resistant Prostate Cancer
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. Metastatic PCa is frequently treated with first-line hormonal ablation therapy. When resistance to this therapy develops, the terminal condition is known as castration-resistant prostate cancer (CRPC). Following the development of 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 PCa. While often initially successful, PCa invariably becomes resistant to this therapy. Multiple mechanisms underlie resistance to LBDT therapy, but two of the more common routes involve aberrant nuclear receptor-mediated transcriptional activation of a number of AR target genes. One scenario involves the glucocorticoid receptor (GR), a nuclear receptor that is expressed more frequently in CRPC. A second scenario involves truncation of the AR to an "always-on" splice variant that is androgen-independent and constitutively active. These variant forms of AR (ARv, particularly ARv7) are resistant to standard-of-care treatment and expression correlates with reduced survival in CRPC patients. While full-length AR and GR, like other nuclear receptors, depend on molecular chaperones, including Hsp40 and Hsp70, for protein folding and ligand binding, it is not known whether ARv, which lack the ligand-binding domain, are similarly dependent on this chaperone network. In exciting preliminary results, we found that CRPC cells that endogenously express GR, AR, and ARv are sensitive to newly identified inhibitors of Hsp40 and Hsp70. We found that ARv retain the ability to bind to both chaperones and that Hsp40/Hsp70 inhibition promotes degradation and inactivation of ARv, as well as of GR and AR. This key observation has led us to hypothesize that the Hsp40/Hsp70 chaperone axis may represent a novel strategy for treating nuclear receptor-dependent CRPC, thus providing the first targeted therapy for this devastating disease. In the proposed work, we will comprehensively explore the mechanisms that link Hsp40 and Hsp70 to the regulation of ARv, and their similarities and/or differences with those of GR/AR. These studies are essential to our understanding of the system and will be critical in the design of effective treatments. In addition to the mechanistic studies, we will explore the efficacy of Hsp40/Hsp70 inhibitors in treating nuclear receptor-dependent CRPC, using both cellular and animal CRPC xenograft models, as well as short-term ex vivo culture of prostate cancer tissue obtained via prostatectomy. These studies will validate the essential role of Hsp40/Hsp70 in this disease and provide the impetus for a detailed preclinical program to progress these chaperone inhibitors to clinical trials in high-risk male PCa populations and those with existing CRPC. The proposed research program is responsive to the goals and mission of the Department of Defense Prostate Cancer Research Program (PCRP). Namely, we will pursue and hope to validate a new drug target, and we will develop a novel strategy to treat CRPC, which remains a major health concern. While current standard of care treatments are transiently effective, they continue to target the AR ligand-binding domain, ultimately leading to a "kicking the can down the road" analogy in that treatment resistance invariably develops after relatively brief intervals. We will explore whether our treatment strategy may also be effective in abrogating or delaying development of resistance in LBDT therapy-naïve patients, as well as in treating patients with existing CRPC. Thus, this research proposal addresses the PCRP Overarching Challenge of developing effective treatments and mechanisms of resistance for men with high-risk or metastatic prostate cancer. Our proposal addre
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610562
Entities
People
- Leonard Neckers
Organizations
- National Cancer Institute
- United States Army