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Principal Investigator: Sukyung Woo
Organization: STATE UNIVERSITY OF NEW YORK AT BUFFALO
Fiscal Year: 2024
Award: $410,155
Funding agency: National Cancer Institute
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 apelin/APJ
axis as an important therapeutic target in HGSOC and provide scientific basis for APJ inhibitors used in
combination with standard-of-care cytotoxics in cytoreductive therapy or as maintenance therapy.
Terms: <3-D><3-Dimensional><3D><APLN><APLN gene><Accounting><Adhesions><Adipocytes><Adipose Cell><Anatomic Sites><Anatomic structures><Anatomy><Anoikis><Antioncogene Protein p53><Anzatax><Area><Ascites><Asotax><Automobile Driving><Basic Research><Basic Science><Biodistribution><Body Tissues><Bristaxol><CDDP><Cancer cell line><Cancers><Carcinoma Cell><Cell Body><Cell model><Cell-Extracellular Matrix><Cells><Cellular Immune Function><Cellular Spheroids><Cellular Tumor Antigen P53><Cellular model><Cessation of life><Characteristics><Chemoresistance><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinical><Co-culture><Cocultivation><Coculture><Coculture Techniques><Computer Models><Computerized Models><Cysplatyna><Data><Death><Diagnosis><Dichlorodiammineplatinum><Disease><Disorder><Dose><Drug Kinetics><Drug Transport><Drug resistance><ECM><Extracellular Matrix><Fat Cells><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><Generalized Growth><Goals><Greater sac of peritoneum><Growth><Health><Heterograft><Heterologous Transplantation><Histology><Human><Immune infiltrates><Immune mediated therapy><Immunocompetent><Immunologically Directed Therapy><Immunotherapy><Implant><In Vitro><Intermediary Metabolism><Invaded><Knowledge><Ligands><Link><Lipids><Lipocytes><Maintenance Therapy><Malignant Cell><Malignant Epithelial Cell><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Mature Lipocyte><Mature fat cell><Mesothelium><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mitochondria><Modeling><Modern Man><Molecular><Multicellular Spheroids><Neoplasm Metastasis><Normal Tissue><Normal tissue morphology><Omental Fat><Omentum><Oncoprotein p53><Operative Procedures><Operative Surgical Procedures><Organ><Outcome><Ovarian><Ovarian Carcinoma><Ovarian Serous Adenocarcinoma><Ovarian Serous Carcinoma><Ovary Cancer><Ovary Carcinoma><P53><PDX model><Paclitaxel><Paclitaxel (Taxol)><Pathologic><Pathway interactions><Patient derived xenograft><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Peritoneal><Peritoneal Cavity><Peyrone's Chloride><Peyrone's Salt><Pharmacokinetics><Phenotype><Phosphoprotein P53><Phosphoprotein pp53><Physiologic><Physiological><Platinum Diamminodichloride><Praxel><Pre-Clinical Model><Preclinical Models><Primary Neoplasm><Primary Tumor><Production><Property><Protein TP53><Receptor Inhibition><Receptor Protein><Reporting><Research><Resistance><Role><Secondary Neoplasm><Secondary Tumor><Serous><Serous Adenocarcinoma of the Ovary><Serous Carcinoma of the Ovary><Site><Surface><Surgical><Surgical Interventions><Surgical Procedure><TP53><TP53 gene><TRP53><Taxol><Taxol A><Taxol Konzentrat><Testing><Therapeutic Intervention><Tissue Growth><Tissues><Toxic effect><Toxicities><Treatment Effectiveness><Treatment Efficacy><Tumor Burden><Tumor Cell><Tumor Load><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Weights><Xenograft><Xenograft procedure><Xenotransplantation><abdominal dropsy><adipocytokines><adipokines><advanced disease><advanced illness><antagonism><antagonist><apelin><barrier to care><barrier to health care><barrier to healthcare><barrier to treatment><cancer cell><cancer metastasis><cancer microenvironment><cancer pharmacology><cancer progression><chemoresistant><chemotherapy><chemotherapy resistance><chemotherapy resistant><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical significance><clinically significant><computational modeling><computational models><computer based models><computerized modeling><cytotoxic><density><driving><drug development><drug distribution><drug efficacy><drug resistant><efficacious therapy><efficacious treatment><established cell line><experiment><experimental research><experimental study><experiments><fatty acid oxidation><female outcomes><genetic approach><genetic strategy><hydroperitonia><hydrops abdominis><immune cell infiltrate><immune competent><immune function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><improved><improved outcome><in vivo><ineffective therapies><ineffective treatment><inhibitor><intervention efficacy><intervention therapy><intraperitoneal><knock-down><knockdown><malignancy><metabolism measurement><metabolomics><metabonomics><migration><mitochondrial><mortality><mouse model><multidisciplinary><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new approaches><novel><novel approaches><novel strategies><novel strategy><obstacle to care><obstacle to healthcare><ontogeny><outcomes among females><outcomes among women><outcomes in females><outcomes in women><ovarian cancer><overexpress><overexpression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><patient derived xenograft model><patient oriented outcomes><peritoneal dropsy><peritoneal exudate><pharmacodynamic model><pharmacologic><pre-clinical><pre-clinical evaluation><preclinical><preclinical evaluation><prevent><preventing><protein p53><receptor><resistance to Drug><resistant><resistant to Drug><social role><spatiotemporal><spheroids><standard of care><surgery><therapeutic effectiveness><therapeutic efficacy><therapeutic target><therapy efficacy><three dimensional><trait><treatment effect><treatment group><tumor><tumor cell metastasis><tumor microenvironment><tumor progression><uptake><women's outcomes><xeno-transplant><xeno-transplantation>