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Principal Investigator: Rugang Zhang
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $439,291
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
the first combinatorial targeted approach for ARID1A-mutated ovarian cancers with a durable outcome. We
show that the inhibition of EZH2 is synthetically lethal with ARID1A mutation. We also show that ARID1A
mutation is synthetically lethal with the inhibition of HDAC6. The objectives of this application are to
investigate mechanisms underlying this newly discovered synthetic lethality and to investigate a combination
therapeutic strategy for ARID1A-mutated ovarian cancer. Our central hypothesis is that targeting EZH2 and
HDAC6 using clinically applicable small molecule inhibitors can achieve a durable therapeutic outcome for
ARID1A-mutated ovarian cancer. Three Specific Aims are proposed: Aim 1 is to investigate the p53-dependent
mechanism by which ARID1A-mutated ovarian cancer cells are selectively sensitive to the inhibition of HDAC6;
Aim 2 will investigate the role of the SWI/SNF complex catalytic subunits switch in determining the sensitivity to
EZH2 inhibitors in ARID1A-mutated ovarian cancer cells; and Aim 3 will investigate the combinatorial therapeutic
strategy for ARID1A-mutated ovarian cancer by simultaneously inhibiting HDAC6 and EZH2. 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 has the potential to develop the first synthetic lethality-based, combinatorial
therapeutic strategy for ARID1A-mutated ovarian cancer with a durable outcome. 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: <3-D><3-Dimensional><3D><ARID1A><ARID1A gene><AT- rich interactive domain-containing protein 1A><AT-rich interactive domain 1A gene><Acetylation><Antioncogene Protein p53><Apoptosis><Apoptosis Pathway><Apoptotic><BRG-1><BRG-1 Gene><BRG1><BRG1 Gene><BRM/SWI2-Related Gene-1><Cancers><Catalytic Core><Catalytic Domain><Catalytic Region><Catalytic Site><Catalytic Subunit><Cell Body><Cells><Cellular Tumor Antigen P53><Chromatin Remodeling Complex><Chromatin Remodeling Factor><Chromatin Structure><Clinical><Data><Deacetylation><Dependence><Diagnosis><Disease><Disorder><Down-Regulation><ENX-1><EZH1><EZH2><EZH2 gene><Endometrioid Adenocarcinoma of the Ovary><Endometrioid Cancer of the Ovary><Endometrioid Carcinoma of the Ovary><Enhancer of Zeste 2 Polycomb Repressive Complex 2 Subunit><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epithelial ovarian cancer><Gene Down-Regulation><Gene Expression><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><HDAC6><HDAC6 gene><Human><Intervention><Intervention Strategies><KIAA0901><KMT6><KMT6A><Knowledge><L-Lysine><LoxP-flanked allele><Lysine><Malignant Cell><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant neoplasm of ovary><Mating Type Switching/Sucrose Nonfermenting Protein><Methods><Mission><Modality><Modern Man><Molecular><Mutate><Mutation><NIH><National Institutes of Health><Oncoprotein p53><Outcome><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><P53><PDX model><Patient derived xenograft><Phosphoprotein P53><Phosphoprotein pp53><Platinum><Platinum Black><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Pre-Clinical Model><Preclinical Models><Primary Neoplasm><Primary Tumor><Prognosis><Programmed Cell Death><Protein Modification><Protein TP53><Pt element><Public Health><Refractory><Research><Resistance><Role><SMARCA4><SMARCA4 gene><SNF2-Beta><SWI/SNF Complex><SWI/SNF Family Complex><SWI/SNF-Related, Matrix-Associated, Actin-Dependent Regulator of Chromatin, Subfamily A, Member 4 Gene><Series><TP53><TP53 gene><TRP53><Testing><Therapeutic><Transcription Repression><Transcriptional Repression><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppressor Proteins><United States National Institutes of Health><Up-Regulation><Upregulation><Xenograft Model><cancer cell><cancer sub-types><cancer subtypes><cancer type><chemotherapy><chromatin modifier><chromatin remodeling><clinical applicability><clinical application><clinical relevance><clinically relevant><combinatorial><effective therapy><effective treatment><epigenetically><experiment><experimental research><experimental study><experiments><feature detection><feature recognition><floxed><floxed allele><gene repression><genetic make-up><genetic makeup><genome mutation><histone deacetylase 6><inhibitor><innovate><innovation><innovative><insight><interventional strategy><malignancy><mouse model><murine model><neoplasm/cancer><novel><ovarian cancer><p53 Antigen><p53 Genes><p53 Tumor Suppressor><patient derived xenograft model><pre-clinical><precision medicine><precision-based medicine><preclinical><protein p53><prototype><resistant><small molecular inhibitor><small molecule inhibitor><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic outcome><therapy outcome><three dimensional><tumor suppressor><xenograft transplant model><xenotransplant model>