The Role of Mitochondrial Metabolism in Prostate Cancer Progression and Susceptibility to Bipolar Androgen Therapy
Abstract
Project Rationale and Objective: Prostate cancer is the second leading cause of cancer mortality in men in the United States despite numerous approved therapies for advanced disease. Therefore, there remains a significant need for improved understanding of prostate cancer pathogenesis and the development of novel therapies. My mentor, Dr. Samuel Denmeade, and colleagues at Johns Hopkins have recently developed a novel therapy, termed Bipolar Androgen Therapy (BAT), in which patients are treated with high-dose testosterone that results in oscillating serum levels of testosterone. BAT was found to have a high response rate in patients with advanced prostate cancer. Yet despite this exciting response, the mechanism of BAT is unknown. This project aims to decipher the mechanism of action of BAT to allow for optimization of this novel therapy. Hypothesis: It is becoming increasingly apparent that one of the major roles of testosterone is to direct cellular metabolism to support the growth of prostate cancer cells. I hypothesize that BAT leads to prostate cancer cell death by reprogramming the cell’s metabolism to rapidly increase lipid synthesis at the expense of fueling other pathways necessary for protein and DNA biosynthesis, energy production, and cellular signaling events. Project Applicability: This proposal directly addresses the FY19 PCRP Overarching Challenge to define the biology of lethal prostate cancer to reduce death. The outlined experiments will define key metabolic pathways that permit prostate cancer cells to thrive and ultimately take human lives. I will determine whether the major effect of BAT is to reprogram these metabolic pathways to lead to prostate cancer cell death. Understanding this mechanism will allow further study to understand why some men fail to respond to BAT; for example, perhaps resistant prostate cancer cells compensate by increasing or changing metabolic flux through a testosterone-independent mechanism. Only when these activating and resistance metabolic pathways are defined can we determine rational drug targets whose inhibition may augment the effect of BAT and lead to a prostate cancer cure. Thus, this project has the potential to help all patients with prostate cancer, though the immediate focus is on development of treatment for men with advanced, imminently life-threatening disease. This project is designed to be performed over a 2-year time period. The data generated from this project are expected to lead to future projects to test inhibition of metabolic targets to augment BAT. I anticipate that this work will lead to clinical trials in patients with prostate cancer in the next 5-10 years. Principal Investigator: I am a first-year fellow in medical oncology at Johns Hopkins Hospital, and my career goal is to become an independent clinician-scientist with a specialty in prostate biology to develop novel therapies targeting cell metabolism to cure prostate cancer. I have expertise in cell biology and the study of cell metabolism from my PhD training. This project will allow me to build on this expertise and to acquire new skills studying prostate cancer biology. Training Strategy: This project has been carefully designed to facilitate my development to an independent investigator. I will work closely with my mentors to refine skills of asking important scientific questions, developing well-designed experiments, and adequately interpreting data. I will acquire technical skills by training with the experienced laboratory members in the Denmeade and Powell laboratories. To improve my written communication skills and disseminate my work, I plan to publish this work in peer-reviewed journals. I will improve my oral communication skills and facilitate collaborations through attending and presenting at institutional and national meetings. Toward the end of this award, I will apply for independent funding. Mentorship Plan: My primary mentor is Dr. Samu
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010079
Entities
People
- Laura Sena
Organizations
- Johns Hopkins University
- United States Army