Project Abstract High-grade serous ovarian cancer (HGSOC) is the most common and lethal histology, accounting for 80% of ovarian cancer death. During peritoneal spread, tumor cells detached form multicellular spheroids (MTS), which survive better unattached and are more resistant to chemotherapy and colonizes better to new sites. They primarily metastasize into lipid-rich areas such as omentum from which cancer cells rely on fatty acid oxidation (FAO) for metastatic progression, survival, and drug resistance. Thus, MTS formation and metabolic adaptation capabilities enable HGSOC cells to adapt in tumor microenvironment and represent critical niches for urgently needed therapeutic interventions. We recently identified a novel target, apelin receptor (APJ) and its ligand apelin that confers such adaptabilities of HGSOC, contributing to treatment inefficacy and metastatic progression. We previously reported the clinical and pathological significance of APJ in promoting HGSOC metastasis and progression. Our new data show that APJ promotes MTS formation, leading to chemoresistant, and reducing MTS by APJ inhibition remarkably increased drug efficacy. Also, adipocyte-derived apelin drives APJ-expressing cancer cells to migrate and invade into lipid-rich tissues, and promote metabolic reprograming to FAO for high energy production. Human xenografts with stable APJ-knockdown HGSOC demonstrated significant reduction in metastatic tumor burden. The primary goals of the proposed research are 1) to expand on our preliminary findings by elucidating the underlying mechanistic roles of MTS formation and metabolism by APJ and the effects of APJ inhibitors in drug resistance and metastasis; 2) to develop a predictive computational model that accounts for the unique physio-cellular characteristics of tumors and anatomical properties in the peritoneal cavity to describe drug transport mechanisms and resulting treatment effects; and 3) leveraging this knowledge to perform the proof-of-concept preclinical evaluation of APJ inhibition in HGSOC and further guide model-informed drug development of APJ inhibitors. Herein, we propose to investigate metabolic effects of APJ and its inhibition in established and primary HGSCO and non-HGSOC cell lines (Aim 1). We will investigate the effects of APJ inhibition of MTS formation on drug efficacy and metastasis in vitro and develop a physiologically-based PK/PD model for peritoneal tumors (Aim 2). We will evaluate the effects of APJ inhibitors alone or combining with chemotherapy in preclinical metastasis models of HGSOC (Aim 3). To accomplish thes goals we have assembled a multi-disciplinary team with expertise in cancer pharmacology and computation modeling (Sukyung Woo); basic research and metabolic pathways of ovarian cancer (Resham Bhattacharya); ovarian cell and mouse model (Raya Huang); and translational and clinical ovarian research and immunotherapy (Kunle Odunsi). Successful completion of this study will establish the ...