The overall goal of the MD Anderson Cancer Center SPORE in Ovarian Cancer is to test and translate novel therapeutic strategies, including those to overcome adaptive resistance to conventional cytotoxic chemotherapy, poly (ADP-ribose) polymerase inhibitors (PARPi), anti-angiogenic agents (bevacizumab) and immune checkpoint blockade. Over the last five years, 1,417 new patients with ovarian cancer received care at MD Anderson. We have prioritized ovarian cancer research through recruitment, salary support, clinical facilities, laboratory space, and philanthropic funds. Philanthropic support from the MD Anderson Ovarian Cancer Moon Shot has provided organization and infrastructure, but the work in the SPORE is completely distinct. We successfully implemented measures to increase the recruitment of women and underrepresented minorities to our Developmental Research Program (DRP) and Career Enhancement Program (CEP). Over the last 22 years, our SPORE investigators have contributed over 1280 manuscripts regarding ovarian cancer with 155 in the last four years. Our SPORE has made significant contributions including: 1) conducted the SPORE and EDRN-supported Normal Risk Ovarian Screening Study (NROSS) where 71% of cases have been detected in stage I or II; 2) identified biomarkers that detect 18% of CA125 negative cases; 3) developed a 4-biomarker algorithm that in retrospect detects advanced stage disease 1.4 to 4.8 years earlier than the CA125-based NROSS algorithm; 4) found anti-TP53 autoantibodies elevated 8 months before CA125 and 22 months before diagnosis; 5) observed a 54% objective response rate to anti-angiogenic therapy with aflibercept and docetaxel; 6) completed a trial targeting Dll4; 7) demonstrated that CSF1R inhibitors can deplete macrophages and reduce resistance to anti-VEGF therapy; 8) demonstrated significant activity of the MEK inhibitor selumetinib in low-grade ovarian cancers and completed an international phase III trial of another potent MEK inhibitor trametinib; and 9) developed a robust biomarker panel that predicts response to PARPi and initiation of multiple trials combining PI3K and PARPi in high-grade ovarian cancer. In the proposed SPORE, Project 1 and Project 4 investigators tackle therapeutic resistance to PARP inhibitors and immune checkpoint blockers from multiple directions to speed progress and improve outcomes for women with ovarian cancer. Both projects have the potential to enhance T-cell infiltration in tumors and impart immunologic memory, which is particularly important given the likelihood of this cancer to recur. In Project 2, we will develop a novel TROP2-targeted CAR-NK therapy. In Project 3, we will develop therapy aimed at the tumor microenvironment using a novel EGFL6 targeted monoclonal antibody. Overall, our translational studies conducted in an optimal environment with a multi- institutional team are directed toward improving clinical outcomes of women with ovarian cancer.

Overall NARRATIVE The SPORE will improve outcomes for ovarian cancer patients by using innovative drugs and/or combinations that target drug resistant ovarian cancer cells and tumor-associated blood vessels, based on the abnormalities in each cancer.