Targeting Rb Loss Using BET Inhibition to Reprogram the Prostate Tumor Microenvironment and Enhance the Efficacy of Immunotherapy
Abstract
Recent years have seen exciting developments in our understanding of how to effectively treat patients with metastatic prostate cancer, with significant advances in our ability to characterize tumors, as well as the approval of a number of new therapies that have increased survival in patients with metastatic disease. In other malignancies, one of the most dramatic steps forward in cancer therapy has been the use of tumor immunotherapy, where individuals are treated with agents designed to activate a patient’s own immune system to attack tumor cells. In particular, the use of checkpoint blockade (a type of immunotherapy designed to “take the brakes off” anti-tumor immune responses) has revolutionized the treatment of a number of previously incurable diseases, providing dramatic and durable clinical responses. However, these responses have been largely absent in prostate cancer, where these agents have failed to elicit the dramatic clinical benefits seen in other cancers. As such, finding specific alterations that result in this lack of clinical response is of the utmost importance in effectively incorporating these agents into the treatment of advanced prostate cancer. Our research has shown that one of the reasons checkpoint blockade may not work in prostate cancer is due to the lack of a “T cell-inflamed gene signature,” which characterizes a patient’s tumor for the presence of immune cells that have the potential of killing tumor cells. We have that found more than 90% of prostate cancer patients lack this signature, and these individuals also have an increased frequency of deletion of the retinoblastoma (Rb) gene, which plays a critical role in tumor cell growth and is not only altered in prostate cancer (particularly in patients with metastatic, castrate-resistant disease), but is one of the most commonly altered proteins across all cancers. Additionally, we have shown that tumors from patients lacking Rb also have decreased killer immune cells and other markers associated with anti-tumor immune responses, which may explain why these patients fail to respond to immunotherapy. As such, finding a way of reversing the effects of Rb loss may provide a way of reprogramming these tumors to promote anti-tumor immune responses. A challenge in targeting the effects of Rb loss is that Rb regulates many different signaling pathways that promote tumor growth, including pathways involved in anti-tumor immune responses. However, one type of treatment that can alter these pathways is the use of epigenetic modulators, which make specific changes to the nature of tumor cell DNA and ultimately change what is produced by these cells. One class of epigenetic agents targets a class of proteins called bromodomain and extra-terminal (BET) domain proteins, which are proteins involved in regulating the activity of Rb. Inhibitors of BET proteins decrease tumor growth (including prostate cancer) and can also enhance anti-tumor immune responses. As such, these agents could be a rational means of targeting Rb-deficient prostate cancer to enhance clinical responses to checkpoint blockade. This proposal seeks to answer this question, testing the underlying hypothesis that Rb-deficient cancer is associated with a lack of anti-tumor immune responses, and these tumors can be selectively targeted using BET inhibition. To test this hypothesis, we will focus on three specific areas of research. We will first examine how Rb loss decreases anti-tumor immune responses in prostate tumors and whether these Rb-deficient tumors can be reprogrammed using BET inhibition. To address this research question, we will utilize tumor samples from patients with prostate cancer, as well as develop a novel mouse model of Rb-deficient prostate cancer. We will then examine how Rb loss contributes to the generation of castrate-resistant prostate cancer (CRPC) and how BETi is able to limit the development and progression of CRPC. Finally, we will use this
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910840
Entities
People
- Brian Olson
Organizations
- Emory University
- United States Army