Interrogating PP2A to understand and treat high-grade endometrial carcinoma

Uterine cancer is the only cancer type for which survival has fallen in the past four decades. This year in the United States, over 13,000 women will die from this disease, surpassing ovarian cancer for the first time: making uterine cancer the deadliest gynecological cancer. Mortality from uterine cancer is primarily due to the aggressive high-grade subtypes of endometrial carcinoma, which include endometrial serous carcinomas, uterine carcinosarcomas, and high-grade endometrioid carcinomas. Molecularly, these high-grade subtypes harbor few mutations, however, almost every high-grade endometrial carcinoma harbors a TP53 mutation, and 30-40% also harbor a heterozygous PPP2R1A mutation, most commonly - P179R, S256F, or R183W. PPP2R1A encodes for the AƒÑ scaffolding subunit of the heterotrimeric protein phosphatase 2A (PP2A). However, a lack of models, particularly transgenic mouse models, of high-grade endometrial carcinomas has limited our understanding of the disease and the preclinical testing of targeted therapeutics directed at the underlying drivers of disease development and progression. Knockout of p53 in mouse endometrial epithelium has been shown to result in the formation of microscopic incompletely penetrant endometrial tumors at 16-20 months of age. Our group has generated novel conditional Ppp2r1a-P179R and R183W knock-in mice. We crossed these mice to the Trp53fl/fl and Ksp1.3-Cre mouse to generate endometrial epithelium-specific knockout of Trp53 and knock-in of either AƒÑ- P179R or R183W PP2A mutant alleles. Preliminary data demonstrate that our mice develop advanced highgrade endometrial carcinomas as early as 5 months of age with 100% penetrance, supporting that PPP2R1A is a driver of high-grade endometrial carcinomas for the first time. Treatment options for advanced high-grade endometrial cancers are limited. Therapeutically, we have developed a series of first-in-class PP2A molecular glues (PMGs) that can specifically stabilize the tumor suppressive PP2A A/B56£\/C heterotrimer. Interestingly, we have found that PMG treatment results in tumor regressions in a dose-dependent manner in PP2A mutant models of high-grade endometrial cancer. Our central hypothesis is that PP2A mutants promote high-grade endometrial tumorigenesis and the Ksp1.3-Cre/Tp53fl/fl/PPP2R1A-mutant mouse models may represent a novel mouse model for tumor development, progression, and detection and molecular glues targeting of PP2A could be a novel treatment strategy for these tumors. The aims of this proposal were formulated to explore the role of PP2A in high-grade endometrial cancer in three predominant areas all of which are NCI mission areas for women¡¦s health research; 1) tumor initiation and progression, 2) modulation of this protein family as a treatment strategy, and 3) substrates regulated by PP2A, which may serve as screening biomarkers of the disease. The use of mice is a crucial component of this proposal as we seek to establish a novel mouse model of high-grade endometrial cancer and test the efficacy of novel therapeutics against high-grade endometrial cancers in vivo. Mice are currently the gold standard for modeling cancer, and we have proposed to test immunotherapy agents, which can only be performed in animal models with intact immune systems. Project Number: 1R01CA307725-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Caitlin O'Connor (+1 co-PI) | Institution: UNIVERSITY OF MICHIGAN AT ANN ARBOR, ANN ARBOR, MI | Award Amount: $512,292 | Activity Code: R01 | Study Section: Cancer Prevention Study Section[CPSS] View on NIH RePORTER: https://reporter.nih.gov/project-details/11268799