Exploiting Dysregulation of Cholesterol Homeostasis as a Novel Therapy for Prostate Cancer
Abstract
Rationale: Prostate cancer is the most common cancer in men after skin cancers. After detection, prostate tumors are commonly treated with androgen deprivation therapy (aka hormone therapy) to reduce levels of androgen (testosterone) in the body, a key growth factor for prostate cancers. Though hormone therapy is initially effective in treating advanced prostate cancer, over time, patients will continue to progress and develop a more aggressive form called castration-resistant prostate cancer (CRPC). Despite hormone therapy, many studies have shown that CRPC tumors can make their own androgens using cholesterol, which is the essential building block for androgens. It is also well known that prostate cancer cells accumulate high levels of cholesterol, which suggests that the mechanism to balance normal levels of cellular cholesterol is dysfunctional. In order to determine the cholesterol-related genes that are not functioning properly in prostate cancer cells, we examined multiple cholesterol-related genes and found that CYP27A1, an enzyme that normally converts cholesterol to 27-hydroxycholesterol (27HC) in the first step of cholesterol breakdown and excretion from the cell, is commonly lost in many prostate cancers. When we restore CYP27A1 expression in prostate cancer cells that have lost CYP27A1, we observed an increase in 27HC levels, reduction in prostate cancer cell growth, and a decrease in cholesterol levels in the cell. Likewise, direct treatment with 27HC, the key product of the CYP27A1 enzyme, reduced prostate cancer cell proliferation and also reduced cholesterol levels in the cell. In addition, we found that treatment with 27HC inhibits activity of the androgen receptor (AR), likely due to decreased conversion of cholesterol to androgens, which activate the AR. Finally, either restoring CYP27A1 or treatment with 27HC slowed growth of CRPC tumors in mice that either don t express the AR or are resistant to hormonal therapy. As all of these pathways (via AR and independent of AR) may contribute to CRPC and all of them can be targeted by 27HC, we propose that restoring CYP27A1/27HC activity can prevent CRPC, though this is as yet untested. Hypothesis and Objective: High serum cholesterol and cholesterol within the tumor may aid the development of CRPC by providing the essential precursor for the tumor to make its own androgens. This led us to hypothesize that lowering cholesterol levels both in the circulation by diet and cholesterol blockers and in the tumor with 27HC will delay the development of CRPC. Our objective is to test this hypothesis to determine whether 27HC is a novel therapy for the prevention of CRPC. To this end, we will test the effects of 27HC on delaying the development of CRPC in castrated mice on high cholesterol diets, alone or in combination with cholesterol lowering agents/diets, and alone or in combination with statins. In addition, we know that 27HC acts in part via a group of nuclear signaling proteins in the Liver X Receptor (LXRs) Family, but that 27HC also works independently of LXRs. Thus, we will conduct a genomics study to identify the additional gene targets of 27HC action in order to find other targets, which we will test to determine whether we can exploit them for CRPC prevention or therapy. If successful, future studies can test whether drugs against these new targets can be used clinically to prevent CRPC. Lastly, we will utilize pre-existing prostate cancer tissues to assess the status of CYP27A1/27HC, cholesterol, and androgens in tumors and determine how these correlate with AR activity and ultimately the risk of developing CRPC. Applicability: Most prostate cancer-related deaths are due to CRPC. To alleviate the number of deaths due to prostate cancer, the goal of this project is to understand the role of cholesterol in CRPC and determine whether we can develop a novel innovative approach to prevent the development of castration resistance. Becaus
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710489
Entities
People
- Stephen J. Freedland
Organizations
- Cedars-Sinai Medical Center
- United States Army