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Principal Investigator: Rugang Zhang
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $465,225
Funding agency: National Cancer Institute
Project Summary
ARID1A, encoding a subunit of the SWI/SNF chromatin-remodeling complex, is the most frequently mutated
epigenetic regulator across human cancers. Most notably, inactivating mutations in ARID1A occur in ~50% of
ovarian clear cell carcinomas (OCCC) and ~30% of ovarian endometrioid carcinomas (OEC). There is an
unmet need for effective treatment modalities for ARID1A-mutated ovarian cancers. For example, OCCC is
generally refractory to standard agents used to treat epithelial ovarian cancer, and when diagnosed in
advanced stages, OCCC carries the worst prognosis of all ovarian cancer subtypes. The overall goal of this
proposal is to develop a novel therapeutic strategy for ARID1A-mutated ovarian cancers by combining a
clinically applicable metabolic glutaminase inhibitor with an immune checkpoint blockade. We show that the
ARID1A inactivation creates a dependence on the glutamine metabolism. We also show that ARID1A
inactivation sensitizes ovarian cancer to anti-PD-L1 treatment. The objectives of this application are to
investigate the mechanisms underlying the dependence on the glutamine metabolism created by ARID1A
inactivation and to investigate a combination therapeutic strategy for ARID1A-mutated ovarian cancer. Our
central hypothesis is that ARID1A-mutated ovarian cancer can be therapeutically eradicated by the
combination of a clinically applicable glutaminase inhibitor such as CB-839 and an anti-PD-L1 immune
checkpoint blockade. Two Specific Aims are proposed: Aim 1 is to investigate the mechanism underlying the
dependence of ARID1A mutation on the glutamine metabolism; and Aim 2 will develop a novel therapeutic
approach for ARID1A-mutated ovarian cancer by combining a clinically applicable glutaminase inhibitor and
anti-PD-L1. The proposed studies are highly innovative because they challenge current research/clinical
paradigms and utilize innovative methods to explore new intervention strategies for ARID1A-mutated ovarian
cancers. The research proposed is of high impact because it will provide a scientific rationale for developing
urgently needed novel therapeutic strategies by repurposing the clinically applicable glutaminase inhibitor CB-
839 and an FDA-approved immune checkpoint blockade for ARID1A-mutated ovarian cancer, a disease that
currently has no effective therapy. Since ARID1A is the most frequently mutated epigenetic regulator across
human cancers, the mechanistic insights gained from the current studies will have broad implications for many
different types of cancers as well.
Terms: <ARID1A><ARID1A gene><AT- rich interactive domain-containing protein 1A><AT-rich interactive domain 1A gene><Aspartate><B220><BRG-1><BRG-1 Gene><BRG1><BRG1 Gene><BRM/SWI2-Related Gene-1><Breast Cell Glutaminase><CD45><CRISPR><CRISPR/Cas system><Cancer Model><CancerModel><Cancers><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cell Body><Cells><Chromatin Remodeling Complex><Chromatin Remodeling Factor><Chromatin Structure><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats><Complement><Complement Proteins><DNA Replication><DNA Synthesis><DNA biosynthesis><Data><Dependence><Diagnosis><Disease><Disorder><EC 3.5.1.2><Endometrioid Adenocarcinoma of the Ovary><Endometrioid Cancer of the Ovary><Endometrioid Carcinoma of the Ovary><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial ovarian cancer><FDA approved><GA Protein><GP180><Gene Transcription><Generalized Growth><Genetic><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><Gln><Glutaminase><Glutamine><Goals><Granzyme><Growth><Human><Immune infiltrates><Immunocompetent><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunosuppressed Host><Intermediary Metabolism><Intervention><Intervention Strategies><Knock-out><Knockout><Knowledge><L glutamine amidohydrolase><L-Aspartate><L-Glutamine><LY5><Liver Glutaminase><LoxP-flanked allele><Malignant Cell><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Mediating><Metabolic><Metabolic Processes><Metabolism><Methods><Mice><Mice Mammals><Mission><Modality><Modern Man><Molecular><Murine><Mus><Mutate><Mutation><NIH><National Institutes of Health><Nucleotide Biosynthesis><Nucleotide Synthesis><Ovarian Clear Cell Cancer><Ovarian Clear Cell Carcinoma><Ovarian Clear Cell Neoplasm><Ovarian Clear Cell Tumor><Ovarian Endometrioid Adenocarcinoma><Ovarian Endometrioid Cancer><Ovarian Endometrioid Carcinoma><Ovary Cancer><PD-L1 antibody><PD-L1 therapy><PD-L1 treatment><PDL1 antibody><PDL1 therapy><PDL1 treatment><PDX model><PTPRC><PTPRC gene><Patient derived xenograft><Platinum><Platinum Black><Prognosis><Pt element><Public Health><Purines/Pyrimidines/Nucleotides/Nucleic Acids Metabolism><Q Levoglutamide><Q. Levoglutamide><RNA Expression><Refractory><Repression><Research><Role><SMARCA4><SMARCA4 gene><SNF2-Beta><SWI/SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 4 Gene><T-Cell Proliferation><T200><Testing><Therapeutic><Tissue Growth><Transcription><Tumor Suppressor Proteins><United States National Institutes of Health><Up-Regulation><Upregulation><Xenograft Model><aPD-L1><aPD-L1 antibodies><aPD-L1 therapy><aPD-L1 treatment><aPDL1><anti programmed cell death ligand 1><anti programmed cell death ligand 1 therapy><anti programmed cell death ligand 1 treatment><anti programmed cell death protein ligand 1><anti programmed cell death protein ligand 1 therapy><anti programmed cell death protein ligand 1 treatment><anti-PD-(L)1><anti-PD-L1><anti-PD-L1 antibodies><anti-PD-L1 monoclonal antibodies><anti-PD-L1 therapy><anti-PD-L1 treatment><anti-PDL-1><anti-PDL1><anti-PDL1 antibodies><anti-PDL1 therapy><anti-PDL1 treatment><antiPD-L1><antiPDL1><cancer cell><cancer microenvironment><cancer sub-types><cancer subtypes><cancer type><check point blockade><checkpoint blockade><chemotherapy><chromatin modifier><clinical applicability><clinical application><complementation><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><effective therapy><effective treatment><epigenetically><experiment><experimental research><experimental study><experiments><feature detection><feature recognition><floxed><floxed allele><genome mutation><human model><immune cell infiltrate><immune check point blockade><immune checkpoint blockade><immune competent><immunosuppressed patient><in vivo><inhibitor><innovate><innovation><innovative><insight><interventional strategy><malignancy><model of human><mouse model><murine model><mutant><neoplasm/cancer><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><nucleotide metabolism><ontogeny><ovarian cancer><patient derived xenograft model><pre-clinical><preclinical><prototype><social role><tumor><tumor microenvironment><tumor suppressor><xenograft transplant model><xenotransplant model><αPD-L1><αPD-L1 antibodies><αPD-L1 therapy><αPD-L1 treatment><αPDL1>