Project 2: Impact of Race and the Microbiome on the Progression and Treatment of Endometrial Cancer
Background and Rationale
- Obesity and insulin resistance are associated with higher risk and worse outcomes for endometrial cancer.
- Obesity has been linked with chemoresistance, due to underlying metabolic dysfunction.
- Non-Hispanic Black women suffer a higher mortality from endometrial cancer than Non-Hispanic White women.
- Worse outcome molecular subtypes? Obesity and diabetes? Other biological factors? Microbiome?
The gut microbiome is known to affect biologic pathways for both obesity and cancer. The microbiome is also thought to simultaneously impact progression of cancer as well as efficacy and toxicity of chemotherapy and immunotherapy.
However, there are many unanswered questions in regards to the microbiome such as:
- What about the uterine microbiome and how does it influence the progression and treatment endometrial?
- Are there racial differences in the uterine and gut microbiome?
- Does molecular subtype of endometrial cancer align with race and subsequently influence the microbiome?
- Thus, the question that we hope to address with this project is could there be a possible inter-relationship between the microbiome (gut and uterine), racial disparities, obesity and endometrial cancer?
- Determine the association between race and the uterine microbiota of post-menopausal, obese Non-Hispanic Black versus Non-Hispanic White women with endometrial cancer.
- Characterize the gut microbiota over time of post-menopausal, obese Non-Hispanic Black versus Non-Hispanic White women undergoing standard-of-care P/C chemotherapy for advanced endometrial cancer and correlate with treatment response.
- Explore whether endometrial cancer simultaneously affects the uterine and gut microbiota using unique pre-clinical models.
Significance and Impact
- Establish for the first time that race and race-related molecular subtypes shape the microbiota in the uterus and gut of women and mice with reciprocal impact on progression or treatment of endometrial cancer.
- Delineate prospectively for the first time the evolution of gut microbiota as Non-Hispanic Black vs Non-Hispanic White women undergo hysterectomy and standard-of-care paclitaxel/carboplatin, and correlate with therapeutic response.
- Develop and use molecularly characterized patient-derived xenograft models from both Non-Hispanic Black and Non-Hispanic White patients with advanced stage endometrial cancer as tools to explore the inter-relationships among race, molecular subtype, and the malignant uterine and gut microbiome on endometrial cancer progression. This is reverse translational as it focuses on endometrial cancer and the microbiota in mouse models using new methodologies (racially diverse patient-derived xenograft preclinical models) derived from patients, inspired by clinically observed disparities.
- Integration of microbiome profiling with multi-omics, metabolomic and transcriptomic profiling (host and microbial) as well as cross-species comparisons between mice and women with endometrial cancer is novel for this proposal. It will facilitate discovery of the underlying mechanisms of differential microbiota profiles that occur with Non-Hispanic Black race and Non-Hispanic Black-related molecular subtype in endometrial cancer, potentially leading to more aggressive disease, critically impacting response to chemotherapy and hence influencing the choice of management and treatments that could be tested in future P50 phase research.
- Strengths of this study include:
- Availability of racially diverse endometrial cancer patient population at UNC-Chapel Hill for enrollment.
- Feasibility supported by preliminary data in mice and women.
- Interdisciplinary group of investigators.