Study of the Role of EZH2 in the Regulation of Macrophage Polarization in Prostate Cancer Tumoral Microenvironment
Abstract
Scientific Objective and Rationale: Despite the advances in treatment options, metastatic prostate cancer (PCa) is the second leading cause of cancer-related deaths in men across the U.S. and Europe and remains incurable. Solid tumors, such as PCa are composed by neoplastic and non-neoplastic cells, including immune cells, and it has been widely reported that the tumoral microenvironment (TME) is an important regulator of primary tumor growth and metastatic spread to distal sites. Unfortunately, despite the introduction of immunotherapies like checkpoint inhibitors has changed cancer patient care, metastatic, and lethal PCa remains one of the poorest responders to these strategies. Therefore, activation of the immune system towards prostate tumor cells remains an attractive treatment strategy. Tumor associated macrophages (TAMs), the principal immune components of PCa TME, represent a major barrier for immunotherapy efficacy in PCa patients and there is a compelling need for understanding the mechanisms implicated in their polarization to improve the therapeutical arsenal available in clinic. Recently, the lab reported that the inhibition of the enhancer of zeste homolog 2 (EZH2), overexpressed in PCa patients, in combination with PD-1 treatment has significant therapeutic benefit. Specific to this application, they observed the reprogramming of TAMs from a tumor immunosuppressive phenotype to an anti-tumor phenotype following EZH2 inhibition. While the activity of EZH2 in TAMs has been reported, the importance of these processes and the exact mechanism/s whereby EZH2 reprograms TAMs has not been extensively studied in PCa. Further, given the potential of chimeric antigen receptor (CAR) mediated immunotherapy and the association of the PCa TME with TAMs, we propose to provide proof-of-concept for the use of CAR-iMacs to prevent PCa progression. Applicability of Research: The proposed research project aims to help patients in two ways. First, will deliver a deeper molecular understanding for the epigenetic regulation of TAMs polarization in the development of an immunosuppressive TME which promotes lethal PCa stages and secondly generating and validating novel immunotherapy treatment strategies in preclinical models. My Goals in Prostate Cancer Research: It is my goal to become an independent PCa researcher, to contribute to our understanding of lethal PCa development, and to generate novel and effective therapeutic strategies that can be translated successfully to the clinic. My proposal draws on previous work from our laboratory that highlights key role of the inhibition of epigenetic regulators to potentiate the efficacy of the check point inhibitor, anti PD-1 therapy, in PCa mouse models. Given my own experience with in vivo models of PCa, the study of different immune cells presented in the TME and the significant translational research expertise of my mentors, Drs. Leigh Ellis, Edwin Posadas, and Saul Priceman, I believe that I am well placed to pursue and achieve the goals of the proposed research. Further, the opportunity to pursue this project as a postdoctoral fellow at the Cedars Sinai Medical Center offers me an invaluable opportunity for professional development in the field of PCa research. I will also extend my knowledge of epigenetics and the generation of models of PCa that will add depth and breadth to the cancer genetics research that I conduct, as well as clinical relevance that will improve the chances of the clinical translation of my findings. I believe this training opportunity will allow me to make an impactful contribution to the field and demonstrate my potential as an independent researcher. Contributions of This Study to Prostate Cancer Research: Significant progress has been made in characterizing the molecular tumor landscape that leads to lethal PCa; however, translation of these findings into clinical outcomes for patients has been limited. In the proposed research, w
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310304
Entities
People
- Beatriz German Falcon
Organizations
- Cedars-Sinai Medical Center
- United States Army