PROJECT SUMMARY Gynecological malignancies such as uterine cancers [e.g carcinosarcomas, papillary serous carcinoma, and leiomyosarcomas (LMS)] and ovarian cancers [e.g low-grade serous and clear cell ovarian cancer] are a significant cause of cancer mortality for women. These uterine cancer subtypes are aggressive with high recurrence rates affecting more black women who are 2 times more likely to die from disease than white women. These ovarian cancer subtypes are chemo-resistant with <10-20% of patients responding to standard of care (SOC) platinum-based chemotherapy. Lack of effective therapies for these gynecologic cancers, is likely due to the lack of robust preclinical models for research for these disease subtypes. My laboratory has developed a preclinical drug development platform to identify new treatment options that exploiting genetic vulnerabilities in high grade serous ovarian cancers (most common subtype) with the ultimate goal to move them into clinical trials for patients. We have developed ~140 PDX models with a >90% take rate, previously prioritizing high grade serous ovarian cancer. We have demonstrated that PDX models and primary tumor cultures maintain characteristics of the patient’s original tumor, including mutation status, gene expression, and clinical behavior. Furthermore, transplantation of patient tumors orthotopically to the mouse ovary/fimbria or uterine horn emulates the natural progression of HGSOC and EMCA, respectively. In addition, we have used this PDX platform to identify new drug combinations to overcome drug resistance in PDX models and then move therapies into clinical trials based on our results. After demonstrating combination PARP and ATR inhibition reverses PARPi resistance in BRCA mutant PDX models, we validated these findings in the clinic in BRCA mutant HGSOC patients showing a 50% response rate for PARPi (olaparib) with ATRi (ceralasertib) in PARPi resistant disease (NCT03462342). Our ultimate goal is to develop new effective treatments for these less common subtypes of gynecological cancers addressing a clinically unmet need. We propose the following project Aims: Specific Aim 1: Develop and molecularly characterize orthotopic PDX and organoid models from gynecological cancers lacking therapies. Specific Aim 2: Evaluate a novel combination therapy in TP53 wild type gynecological cancer organoids and PDX models. These studies will ultimately provide molecularly characterized preclinical models, for ovarian and uterine cancer subtypes, currently lacking in vitro and PDX models. These models will be shared with the scientific community to expedite drug development in these rarer but deadly gynecological cancers. In addition, we will validate preliminary in vitro studies showing synergistic activity of a new combination therapy, in already established PDX models. Studies may support moving a new drug combination into clinical trials through CTEP and NRG Oncology.