Cotargeting of Androgen Synthesis and Androgen Receptor Expression as a Novel Treatment for Castration-Resistant Prostate Cancer
Abstract
Men with advanced and metastatic prostate cancer are treated with hormone therapy, either surgically or pharmacologically, also known as androgen deprivation therapy (ADT), by which the signaling initiated by male hormone androgens is inhibited or suppressed. The principle of ADT is that the growth of prostate cancer cells is dependent on the signaling initiated by the binding of androgens to the androgen receptor (AR). Although most patients show a good response to ADT initially, the majority of patients generally experience relapse within 2-3 years, and prostate cancer cells become refractory to the treatment, a status previously named as hormone refractory prostate cancer and now renamed as castration-resistant prostate cancer (CRPC). CRPC is a lethal status of the disease, and it is the major contributor of prostate cancer morbidity and mortality. The major mechanism underlying the development of CRPC is the reactivation of the AR signaling, here referred to as AR reactivation. AR reactivation mechanisms include AR overexpression, AR mutations, AR splice variants, and androgen-independent activation of AR by AR modulators as well as de novo androgen synthesis in prostate cancer cells. In fact, the next-generation anti-androgen drug abiraterone was approved by the Food and Drug Administration in 2011 for CRPC treatment because of its ability to inhibit CYP17A1, a critical enzyme involved in the de novo androgen synthesis in prostate cancer cells. Unfortunately, AR reactivation remains a major mechanism of resistance to abiraterone as well as to another next-generation anti-androgen drug, enzalutamide. Therefore, there is an urgent need to develop novel therapeutic approaches that can overcome AR reactivation for CRPC treatment. We have recently discovered that protein arginine methyltransferase 5 (PRMT5), an emerging enzyme that can control the expression of target genes, is overexpressed in prostate cancer tissues, and its expression positively correlates with the expression of AR. Preliminary data strongly suggest that PRMT5 regulates prostate cancer cell growth in both hormone naïve prostate cancer cells and in CRPC cells in an AR-dependent manner. Because PRMT5 regulates AR expression through an epigenetic mechanism, by which the expression of AR, AR mutants, or AR splice variants are all under the control of PRMT5, targeting PRMT5 will likely overcome most, if not all, AR reactivation mechanisms by eliminating the expression of all forms of AR including AR mutants and AR splice variants. Thus, we hypothesize that co-targeting androgen synthesis and AR expression simultaneously will overcome the mechanisms of AR reactivation and provide an effective treatment for CRPC. To test this hypothesis, we will first examine whether PRMT5 regulates expression of AR in multiple CRPC cell lines. Next, we will use a genetic approach to reduce the expression of PRMT5 or a pharmacological approach to inhibit PRMT5 activity with newly developed inhibitors as PRMT5 targeting approaches to evaluate whether PRMT5 targeting in combination with the inhibition of androgen synthesis by abiraterone shows a better inhibitory and/or killing effect in multiple CRPC cell lines. Finally, we will use CRPC cell lines as well as two patient-derived xenograft (PDX) lines to establish xenograft tumors in mice and test whether inhibition of PRMT5 by a small molecule inhibitor in combination with abiraterone provides a better treatment effect to suppress tumor growth or kill tumors in mice. Contrary to the current approaches to inhibit AR activity, the proposed PRMT5 targeting is to eliminate the expression of AR. Because AR reactivation is the major underlying mechanism of CRPC development and of resistance to abiraterone and enzalutamide, the proposed elimination of AR expression by PRMT5 targeting in combination with abiraterone represents a novel and unique approach to treat CRPC. Given that two PRMT5 small molecule inhibitors
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610394
Entities
People
- Chang-deng Hu
Organizations
- United States Army
- University of Virginia