Harness the Gut Microbiome to Improve Endocrine-Targeted Therapy Response in ER+ Breast Cancer
Abstract
The human body contains more bacterial cells than human cells. Therefore, it is unsurprising that the gut microbiome plays a critical role in the development of disease. Menopause was shown to shift the gut microbiome. Literature indicates that postmenopausal women display decreased gut bacterial diversity when compared to BMI-matched premenopausal women. These gut microbial effects are similar to the effects of obesity on gut microbiome. Postmenopausal women also had higher levels of pro-inflammatory cytokines, suggesting key interactions between estrogen, microbiota, and inflammation. Over 281,000 new cases of breast cancer are diagnosed annually within the United States. The majority are estrogen receptor-alpha positive (ER+), and these patients are often treated with adjuvant endocrine-targeted therapies to prevent tumor recurrence. These therapies include aromatase inhibitors (AIs; letrozole) or selective estrogen receptor modulators (SERM; tamoxifen). While initially effective, resistance can develop over time, thereby limiting therapeutic efficacy. Therefore, understanding the mechanisms driving therapeutic resistance and developing novel strategies to potentiate drug efficacy is critical to prevent breast cancer recurrence and reduce mortality. We suggest that oral endocrine targeting therapies shift the gut microbiome populations that can mediate systemic inflammation and estrogen metabolite bioavailability to promote ER+ breast tumorigenesis and therapeutic resistance. Our DOD BCRP Breakthrough Level 2 application addresses three different FY21 Overarching challenges: (1) Identify what drives breast cancer growth, and determine how to stop it. (2) Determine how to prevent lethal recurrence. (3) Revolutionize treatment regimens by replacing them with ones that are more effective and impact survival. The purpose of this study is to investigate whether oral endocrine targeted therapies shift the gut microbiome and the function of these gut population in regulating drug response. We will validate our non-human primate, preclinical murine studies, and our human ex vivo colon bioreactor preliminary findings with human clinical samples from AI-treated patients (before the start of therapy and after 3 months of therapy) from a donor-sponsored clinical trial performed at the Wake Forest University Comprehensive Cancer Center. Furthermore, we aim to determine the impact of targeting a specific gut microbiota population (ß-glucuronidase GUS-expressing microbes that can regulate estrogen metabolite excretion), in enhancing tamoxifen therapy responsiveness in a metastatic ER+ syngeneic mouse model of breast cancer. Once we establish the role of gut microbes in facilitating endocrine therapy response, we can determine the best way to target the gut microbiome to improve ER+ breast cancer outcomes. Moreover, we can design effective combinatorial therapeutic and interventional approaches (diet or GUS inhibitors) to shift the gut microbiome to increase responsiveness and limit lethal recurrence of breast cancer. Long-term goals include development of a clinical trial to target the gut microbiome in ER+ breast cancer patients undergoing adjuvant endocrine therapy to increase therapeutic response to ultimately reduce breast cancer mortality.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210055
Entities
People
- Katherine Cook
Organizations
- United States Army
- Wake Forest University