Precision Targeting of Cell Cycle Checkpoints in TP53-Mutant Endometrial Cancer
Abstract
This proposal focuses on the Peer Reviewed Cancer Research Program (PRCRP) Topic Area Endometrial Cancer and the Military Health Focus Area of improving Mission Readiness by overcoming gaps in treatment. Endometrial cancer is the most common gynecologic malignancy in the United States. Many women are cured through surgical removal of the uterus; however, once endometrial cancer spreads beyond the uterus there are limited therapeutic options. The most lethal endometrial cancers often carry mutations in a gene called TP53, which encodes the protein p53. p53 has many functions in normal cells including helping cells successfully duplicate and helping cells die when there are problems in the cells. It is not known why p53 mutant endometrial cancers are so aggressive. The scientific objective of this proposal is to understand if mutant p53 can play a role in therapeutic sensitivity and resistance in endometrial cancer, and if so, what the best therapies are for p53 mutant tumors. To help achieve this, the Hill lab has generated multiple models of endometrial cancers to help best study these aggressive tumors. One model is called an organoid, which is a three dimensional model of an endometrial tumor derived directly from a tumor taken from the operating room. Another model is called a co-culture, and this model contains matched organoids and immune cells from the same tumor. The Hill lab obtains endometrial tumors from the operating room, gently dissociates the tumor and immune cells, and then plates the tumor spheres together with those immune cells in a mixture containing either drugs able to target the tumor cells, immune therapies, or combinations of tumor cell targeting and immune therapies. The lab then measures how the immune and tumor cells respond to these therapies using different readouts. This work will utilize a combination of functional and transcriptional studies on organoid and cell lines, organoid co-cultures, and animal models to dissect the role of mutant p53 in therapy response in endometrial cancer, and in so doing, develop new therapies for these aggressive tumors. The Overarching PRCRP challenge to be studied in this work is to transform endometrial cancer treatment through (1) identification of novel biomarkers and new targets, and (2) improving immune therapy. By studying how mutant p53 in endometrial cancer cells impacts the ability of these cells to respond to therapies, we will identify new therapies for endometrial cancer, including drugs that target both tumor cells and enhance the anti-tumor immune response. By gaining this understanding, we may identify biomarkers that can be used to identify which patients will respond to these therapies. Finally, by gaining this mechanistic knowledge, we may benefit all endometrial cancer researchers by spurring discovery of new targetable pathways for which additional therapies can be developed by the broader endometrial cancer scientific community over time. This work is likely to help all patients with endometrial cancer by generating new therapies with paired biomarkers; however, it will be especially beneficial to Hispanic and African American women, who have disproportionately poorer endometrial cancer outcomes. The work will study multiple drugs that have known dosing levels and schedules based on previous clinical use, and we will perform studies both in cell and organoid lines and in animal models to generate extensive preclinical data. We will also work closely with our medical oncology colleague Dr. Ursula Matulonis to evaluate findings for clinical applicability by meeting monthly to discuss progress. Thus, given the known dosing schedules for all agents in this study and the in depth pre-clinical analysis we will be performing, any effective single agent or combination therapies we find can be rapidly translated to clinical trials with Dr. Matulonis’ guidance. Our goal is to work together with Dr. Matulonis to initiate a cl
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210269
Entities
People
- Sarah Hill
Organizations
- Dana–Farber Cancer Institute
- United States Army