An NR Axis as a Novel Determinant of AR in CRPC
Abstract
Most of human prostate cancer tumors contain high amount of the androgen receptor (AR) protein. The AR protein in the prostate tumors also changes to smaller forms (so-called AR-variants), which do not respond to the current anti-androgens such as enzalutamide (ENZ), abiraterone (ABI), or other androgen deprivation therapies. It is believed that the AR changes including its functional changes and highly elevated levels are largely responsible for the tumor progression to castration-resistant status, so-called castration-resistance prostate cancer (CRPC), and to other deadly forms such as the development of ENZ or ABI-resistant, metastatic tumors. More effective targeting of AR or its variants becomes an increasingly urgent, yet highly challenging task. Many current studies are aimed at identifying agents that do not directly addresses the root cause of the problem, namely, the high level of AR production by the tumor cells. Through our preliminary study, we uncovered that a different receptor protein, called RORgamma, is likely responsible for the over-production of the AR proteins and for the changed AR function that drive tumor progression to more aggressive phenotypes including metastasis and therapeutic resistance. More importantly, we found that, in xenograft tumor models, some of the recently developed, new generation of RORgamma-specific small molecule inhibitors, which are developed by pharmaceuticals for potential use in human autoimmune diseases, can potently reduce the AR production and AR function, and strongly inhibit the tumor growth, with desirable safety profile. The objectives of study are the following: (A) To provide solid preclinical evidence that the recently developed, new-generation, small molecule inhibitors of RORgamma developed for human autoimmune diseases are highly efficacious in treatment of models of advanced CRPC; (B) to provide the mechanism of action (MOA) of the inhibitors; and (C) to establish that RORgamma is a novel, key driver of PCa progression. The outcomes of our proposed study will have several, immediate, and long-lasting impacts that are applicable to the development of truly new-generation of prostate cancer drugs that are more effective in treatments of advanced CRPCs. First, it will put the RORgamma inhibitors (newly developed for human autoimmune diseases) onto a "fast-track" for CRPC drug development such as clinical trials for treating patients with advanced, ENZ-resistant, metastatic tumors -- an anticipated, immediate/short-term impact. Several highly promising RORgamma inhibitors that are orally bioavailable and display desirable safety and efficacy have been developed by leading pharma industries for treatment of human autoimmune diseases. Some (e.g., VTP-43742) showed safe and desirable PK and PD profiles in a very recent Phase I trial. Therefore, it is anticipated that our study, once published, will stir tremendous interests in the pharma industries and academics to test their current investigational drug or redirect their autoimmune programs toward clinical development of high-efficacy, truly next-generation drugs for the advanced CRPC. Importantly, the insights into the prostate cancer-specific MOA of the current investigational drugs will be highly valuable in guiding the next-generation CRPC drug development. Second, it will provide novel insights into better understanding of the disease progression -- a long-term impact. Our study, once completed, will shed a bright, new light on current understanding of the disease progression. This is because that RORgamma is likely a master, upstream regulator of AR function and expression in advanced tumors. Thus, the study will open new fronts investigating its function and regulation and other possible RORgamma-like proteins in CRPC progression and for novel therapeutic development.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610583
Entities
People
- Hongwu Chen
Organizations
- United States Army
- University of California, Davis