Targeting HSD3B1-Associated Extragonadal Androgen Biosynthesis to Sensitize Lethal Prostate Cancer
Abstract
Approximately 1 in 7 men will develop prostate cancer and 1 in 40 men in the United States will die of prostate cancer. Commonly, prostate cancer occurs in old age and has an indolent course, and treatments produce excellent outcomes. This study focuses on an aggressive and deadly form of prostate cancer that has a high likelihood of progressing to metastatic disease and developing resistance to hormone therapy. This aggressive form of prostate cancer is marked by the presence of a genetic variation that essentially allows prostate cancer cells to produce their own testosterone. This genetic variation renders many otherwise successful treatments aimed at blocking testosterone signaling ineffective. At least one copy of this gene is inherited at birth in about 40% of men who develop prostate cancer. While advances in DNA technology have permitted easy identification of this variation, which was originally discovered by Dr. Nima Sharifi, the biological underpinnings for the aggressive behavior of prostate cancer in men who inherit this gene remain largely unknown. As such, targeted treatment options for men with this gene, called HSD3B1 (A1245C), continue to elude clinicians. Our research led to the discovery of the function of HSD3B1 (A1245C), which results in stabilization of a protein that produces dihydrotestosterone (DHT) from readily available steroid hormone building blocks. In simple terms, this results in an unlimited supply of “fuel” for prostate cancer cells, even in the presence of most hormone-blocking drugs. We have shown that this commonly inherited gene is associated with more rapid development of metastatic hormone therapy-resistant prostate cancer. In this proposal, we aim to define the role that HSD3B1 (A1245C) is playing in driving therapeutic resistance in both non-metastatic and metastatic prostate cancer and discover why this genetic variation leads to earlier development of lethal metastatic castration-resistant prostate cancer (mCRPC). Our work seeks to link this genetic variation to the DNA damage response that plays a vital role in the efficacy of many anti-cancer therapies directed at selectively damaging prostate cancer DNA. The association between testosterone and DNA damage has been the focus of prior research, which can be summarized as having shown a direct relationship between testosterone signaling and DNA damage induced by radiation, hormone therapy, and/or chemotherapy. We are proposing a combination of basic research and retrospective clinical/translational investigations that will have direct clinical applicability by establishing whether a genetic variant associated with aggressive prostate cancer also modifies tumor response to DNA damaging therapies. If successful, we anticipate that a clinical test for this genetic variation would help doctors select appropriate patient-tailored treatments designed to prevent progression to lethal mCRPC. The timeline of this study is designed to yield preliminary results and insight into the role of this genetic lesion in the treatment of prostate cancer within 3 years, with the expectation of moving promising results forward to clinical studies and improving outcomes in aggressive HSD3B1 (A1245C) prostate cancer. I am personally devoted to a career in prostate cancer translational research, as evidenced by my prior training in genitourinary oncology, clinical focus on prostate cancer patients, and previous research in the field of prostate cancer. I was fortunate as a resident to train in a program with ample opportunity for prostate-focused research. These experiences culminated in a faculty appointment combining my love of cancer medicine with a passion for understanding the basic biology of prostate cancer. Working in one of the nation’s premier urologic institutes allows me access to mentorship from prostate cancer leaders like Dr. Nima Sharifi and Dr. Eric Klein. My overarching objective is to use basic discovery to d
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810177
Entities
People
- Omar Y. Mian
Organizations
- Cleveland Clinic
- United States Army