Adiposity, Nuclear Hormone Signaling, and the Response Phenotype to Androgen Signaling Inhibition in Metastatic Prostate Cancer
Abstract
Survival for men with lethal prostate cancer may be improved by understanding how patient characteristics influence response to treatment. Prostate cancer is primarily driven by androgens, such as testosterone, interacting with the androgen receptor. Blocking androgens (ASI) is the main treatment for metastatic prostate cancer, yet ASI also adversely affects fat and muscle mass in men. Adiposity is a more refined measure of fat tissue than body mass index (BMI), which is commonly used to define obesity. The influence of adiposity on prostate cancer may vary by disease stage or exposure to ASI. For men with localized prostate cancer, increasing adiposity is unfavorable because it increases the risk of death due to prostate cancer. In metastatic prostate cancer that worsened after initial treatment, increasing adiposity is favorable because patients have improved response to ASI, a potential obesity paradox. It is critical to understand whether adiposity levels before exposure to ASI (intrinsic) or the change after exposure to ASI (acquired) affects survival in metastatic prostate cancer. Furthermore, we do not understand how adiposity changes the biology of the prostate cancer to influence survival. We hypothesize that adiposity levels, before ASI and changes in adiposity after exposure to ASI, influence response to treatment in men with metastatic prostate cancer. To test this hypothesis, we propose to study the following: (1) determine where adiposity is associated with response to treatment and steroid hormone levels in metastatic prostate cancer; (2) determine how the genes we inherit, related to steroid hormone production, affect adiposity; and (3) in tissue from prostate cancer, we will determine whether the expression of genes that are related to steroid hormone signaling differs by adiposity. We anticipate that results from our proposed study will address the DOD Overarching Challenges to develop treatments that improve outcomes for men with lethal prostate cancer and define the biology of lethal prostate cancer to reduce death. Our proposal has the potential to help men with metastatic prostate cancer on multiple fronts. First, it begin to optimize the risk-benefit ratio with ASI by helping us understand how a patient’s body composition will affect response to treatment and their risk for body composition toxicity with treatment. Also, our findings could identify a subset of men who are at risk for resistance to ASI, based on their adiposity, through a distinct and targetable pathway: glucocorticoid receptor activity. The greatest potential impact from our work is that we could begin to elucidate the biology behind how host factors, in particular adiposity, affect survival for men with prostate cancer. We expect that these findings could begin to influence patient care in 3-5 years. Regarding the potential therapeutic target, the glucocorticoid receptor, we are uniquely positioned to take the findings from this proposal and evaluate whether it is effective in patients because we are currently leading a phase II clinical trial of a drug targeting the glucocorticoid receptor. Dr. Andrew Hahn’s career goal is to become a clinical investigator focusing on advanced prostate cancer. Specifically, he hopes to develop a longitudinal research program to understand how patient lifestyle characteristics affect response to treatment and survival. Using the knowledge gained from this longitudinal program, Dr. Hahn will design and run clinical trials to evaluate therapeutic interventions that address patient lifestyle characteristics. The research that will result from this proposal will serve as a cornerstone of Dr. Hahn’s investigational career and establish a scientific approach that will be used to evaluate additional lifestyle factors. Dr. Hahn has constructed a multidisciplinary mentorship team who have the expertise to guide the development of this longitudinal research program. Dr. Christop
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210117
Entities
People
- Andrew W Hahn
Organizations
- The University of Texas MD Anderson Cancer Center
- United States Army