Epigenetic Regulators of Lineage Plasticity in Prostate Cancer
Abstract
Scientific Objective: Anti-androgen hormonal therapies are the cornerstone of treatment for men with advanced prostate cancer. Despite initial responses, treatment resistance invariably develops which contributes to the majority of deaths from prostate cancer each year. In up to 20% of cases, prostate cancers bypass therapy and continue to grow by changing their identity. They start to look and act less like prostate cancer and can develop features of neuroendocrine prostate cancer (NEPC). This process, termed lineage plasticity, is associated with loss of hormone dependence and the development of aggressive clinical features. We identified key molecular regulators that drive the development of NEPC by turning on and off important cancer genes and molecular pathways. I hypothesize that these key epigenetic drivers of lineage plasticity can be exploited as therapeutic targets to block or reverse lineage plasticity and arrest the development of NEPC. This proposal will define the mechanisms underlying lineage plasticity in order to develop novel therapeutic interventions to combat treatment resistance in prostate cancer. This study will also evaluate FDA-approved drugs used in the treatment of other cancers using patient-derived preclinical models that represent different stages of prostate cancer. Outcomes and Applicability of the Study: There are no effective therapies available for men with NEPC. Understanding the biology of NEPC will accelerate development of efficient treatment strategies. The experiments proposed in this study build upon extensive preliminary data derived from patients and preclinical models to address a key FY21 PCRP Overarching Challenge: to define the biology of lethal prostate cancer to reduce death. In addition, I will test FDA-approved drugs, namely tazemetostat and decitabine, employed in the treatment of other cancer types in NEPC preclinical models to block the molecular drivers of lineage plasticity. Therefore, the preclinical experiments using these drugs address a second FY21 PCRP Overarching Challenge: to develop treatments that improve outcomes for men with lethal prostate cancer. The focus of this study is on a key molecular driver known as EZH2, which has also been reported to play a role in promoting androgen-dependent prostate cancer growth. Therefore, the results of this study will also contribute to the understanding of androgen-dependent prostate cancer in addition to NEPC, thus potentially impacting more than 20% of patients with advanced prostate cancer. The study will discover the genes and pathways reactivated when these molecular drivers are blocked. This will inform biomarker development that may improve patient selection for clinical trials. These data may also aid in the monitoring of drug response through the development of molecular readouts of drug effect that could be further developed as non-invasive assays. The results of this project could inform clinical trials using FDA-approved drugs within a relative short time period and ultimately impact patient-related outcomes. Career goals of the Principal Investigator: My rigorous Ph.D. experience in a prostate cancer molecular biology laboratory at the Cleveland Clinic instilled a strong determination in me to become an independent prostate cancer researcher. For my post-doctoral training, I chose to expand my knowledge on NEPC and strive to develop novel treatment strategies, under the mentorship of Dr. Himisha Beltran, a world-renowned clinician-scientist. This proposal encompasses essential components that will provide me adequate training to become an expert in using novel preclinical models of prostate cancer, several new molecular biology techniques, and computational approaches and will yield collaboration opportunities. In my research development plan, I have outlined multiple career development and educational programs in the Boston medical area that will help accelerate my care
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210197
Entities
People
- Varadha Balaji Venkadakrishnan
Organizations
- Dana–Farber Cancer Institute
- United States Army