Androgen Receptor-Targeted Treatment for Therapeutically Challenging Breast Cancer
Abstract
Estrogens are female hormones that are important for the development and maintenance of female secondary sexual organs, bone, and other tissues. The functions of these estrogens are mediated by estrogen receptor alpha (ER). Estrogens and their receptor ER also play a role in the development of breast cancers. Continuous treatment of breast cancer with ER-targeting agents will result in a resistant cancer, typically due to mutations in the ER. These mutant ER-expressing breast cancers will stop responding to endocrine therapy and hence have to be treated with toxic chemotherapeutic agents. Similar to estrogens and ER, androgens and their receptor androgen receptor (AR) are important male circulating hormones and their receptor, respectively. AR is another therapeutic target highly expressed in breast cancer that could be targeted to treat refractory breast cancers. Our laboratory has discovered that AR agonists, also called selective androgen receptor modulators (SARMs), are useful for the treatment of different types of breast cancers. We will evaluate the potential of these agents to treat hormone receptor-positive breast cancers. Overarching Challenge: The proposal will address the overarching challenge “Revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival.” Patient Population: The project is expected to benefit women suffering from hormone receptor-positive breast cancers. Potential Clinical Applications: Currently, many breast cancer patients are being treated with toxic chemotherapeutic agents. New therapeutics that are mechanistically superior and less toxic are required to treat these patients. AR agonists will have the potential to treat ER-positive breast cancer. These agonists will not only reduce the growth of the cancer but will also increase bone and muscle mass and also improve sexual function in these women. These drugs are proving to be extremely safe with the AR agonist SARMs have already been used in multiple clinical trials in over 1000 patients. No associated safety issues were noted with these drugs. Projected Time for Patient-Related Outcome: As the AR agonist (SARM or enobosarm) has already been successfully tested in two Phase II clinical trials, it is one step away from becoming available to patients suffering from ER-positive breast cancers. Hence, this project is extremely important to generate compelling mechanistic evidences and associated companion diagnostics to support future clinical trials. Impact: The studies will identify a) new biomarkers and companion diagnostics for future AR-targeted therapeutics and b) novel therapeutics with better understanding of the mechanism of action. The project will address the overarching goal by replacing the current toxic chemotherapy with less-toxic targeted treatment options that will increase the quality of life and potentially survival. Moreover, since AR agonist is proposed as a treatment approach, resistance development due to selective pressure might not be an issue.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110055
Entities
People
- Ramesh Narayanan
Organizations
- United States Army
- University of Tennessee Health Science Center