Targeting EZH2 for Novel Combination Therapeutic Strategies in Aggressive Variant Prostate Cancer
Abstract
Scientific Objective and Rationale: A majority of metastatic prostate cancer (PCa) patients develop resistance to androgen deprivation therapy (ADT), which is the current standard of care for metastatic PCa. Aggressive variant prostate cancer (AVPC) is incurable. An increasing body of work demonstrates that AVPC arises in response to therapy. The transformation of a PCa from a tumor that is initially sensitive to ADT to AVPC involves the acquisition of genetic alterations that ultimately enable PCa cells to survive hormone therapy. Many independent studies, including those conducted in our own laboratory, have highlighted the importance of combinatorial losses of three key tumor suppressors in this mechanism of resistance to therapy, but little progress has been made toward targeting them therapeutically. This research proposes a novel combination therapy approach to prevent or reverse resistance to ADT and progression to AVPC. Applicability of Research: The proposed research project aims to help patients in two ways. First, by investigating genetic and epigenetic drivers that lead to lethal PCa and therapeutic resistance, and second, by identifying and testing the feasibility of utilizing a novel combination therapeutic strategy to reverse or prevent AVPC. My Goals in PCa Research: It is my goal to become an independent PCa researcher, to contribute to our understanding of lethal PCa, and develop 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 genetic changes that occur during progression to AVPC to identify novel strategies to target these pathways. Given my own experience with in vivo models of PCa and the significant translational research expertise of my mentors, Drs. Leigh Ellis and Christopher Sweeney, 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 Dana-Farber Cancer Institute 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 PCa Research: Significant progress has been made in characterizing the molecular tumor landscape that leads to AVPC; however translation of these findings into clinical outcomes for patients has been limited. In the proposed research, we will test the efficacy of using combination therapy therapeutically to target the genetic and epigenetic pathways that result in lethal PCa. Our success will drive the PCa field forward and significantly alter clinical management of patients with AVPC. With the highly relevant preclinical models and drug targeting strategies proposed in this application, we anticipate the results of our work could lead to clinical trials in patients with AVPC within 5 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910305
Entities
People
- Katherine L Morel
Organizations
- Dana–Farber Cancer Institute
- United States Army