BH3-Mimetic Drugs for Prostate Cancer Therapy
Abstract
Scientific Objectives and Rationale for the Proposed Project: Prostate cancer is the most common non-skin cancer diagnosed in men and the second leading cause of death from cancer among men in the U.S. Within the last decade, we have had tremendous progress in combining hormonal treatments and chemotherapies to prolong the lifespan of patients with metastatic disease. Unfortunately, almost all patients develop resistance to therapies. Thus, new therapies are desperately needed. We and others have recently found an alternative strategy to tackle the disease. We discovered that cancer cells are programmed to undergo self-elimination (called apoptosis), but are able to survive by producing anti-apoptotic signals. Specific genomic alterations that are commonly found in prostate cancer sensitize cells to mediations that inhibit these anti-apoptotic signals. In this study, we aim to determine the molecular mechanism of this sensitivity and set the basis for clinical evaluation of medication targeting apoptosis in prostate cancer. Applicability of the Research: Our proposed study aims to develop treatments that improve outcomes for men with lethal prostate cancer, which addresses the first FY20 PCRP Overarching Challenge. To achieve our goal, we will determine the mechanism by which specific genomic alterations and medications inducing cellular stress sensitize tumors to treatments targeting anti-apoptotic pathways (addressing the fourth FY20 PCRP Overarching Challenge, “define the biology of lethal prostate cancer”). However, there is also a rationale for using combination therapies targeting apoptosis earlier, in the first line therapy for castration-sensitive prostate cancer, in order to delay the onset of resistance. This could benefit all men with metastatic prostate cancer. Our results will direct the clinical application of pro-apoptotic treatments in prostate cancer. We expect that, within the first 3 years, we will have a genetic marker to predict which patients benefit from these agents. With the completion of the study, we will also determine the optimal combination therapies for testing in clinical trials. PI’s Career Goals: My overarching goal as a researcher and clinician is to identify and target vulnerabilities of prostate cancer tumors to help my patients live longer. This research will help me develop skills in leadership, biology, genetics, and statistics that are essential to become an independent physician scientist. Data produced from this work will allow me to set the stage for my individual contribution to prostate cancer research and form the basis of future grant applications. In addition to my research endeavors, I am dedicated to treating patients with prostate cancer in clinic. This July, I will officially join as faculty (Instructor in Medicine at Harvard Medical School) the genitourinary team of Beth Israel Deaconess Medical Center. One quarter of my effort will be dedicated to patient care and three quarters to research. My clinic experience will help me identify new areas for research, as well as gain insight to the outcomes and day-to-day effects that matter most to my patients. In a directly translatable way, my research informs my clinical care, and my clinical care inspires research questions to achieve the best outcomes for patients. This relationship between research and clinical care serves as the foundation of my career and fills me with promise for the future of the field. My mentor, Dr. Balk, has over 30 years of experience in the field of prostate cancer research and has successfully mentored over 30 young investigators who have gone on to hold senior academic faculty roles themselves, including field leaders in prostate cancer clinical/translational research. For the last 2 years, we have had a wonderful and productive relationship of mentor-mentee, the scientific product of which is presented in this proposal. He is also my contact person for person
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110471
Entities
People
- Andreas Varkaris
Organizations
- Beth Israel Deaconess Medical Center
- United States Army