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Therapeutic vulnerabilities of ARID1A-mutant and -wildtype ovarian clear cell carcinoma

Award Number: R01CA307360
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Therapeutic vulnerabilities of ARID1A-mutant and -wildtype ovarian clear cell carcinoma - Project summary Ovarian clear cell carcinoma (OCCC) is a rare subtype of ovarian cancer with resistance to chemotherapy and poor prognosis in advanced-stage disease. OCCC is heterogeneous; for instance, about half of OCCC have mutations in ARID1A, encoding a member of the SWI/SNF chromatin remodeling complex. New treatments for OCCC are urgently needed for both ARID1A-mutant and -WT OCCC. Our long-term goal is to develop new therapeutic strategies effective for patients with all subtypes of OCCC. We showed that OCCC is sensitive to inhibition of BCL-XL, pro-survival protein in the intrinsic pathway of apoptosis. Many anti-cancer treatments upregulate pro-apoptotic proteins and enhance dependency upon pro-survival proteins such as BCL-XL. We performed chemical screens to identify compounds active against OCCC alone or in combination with BCL-XL inhibition. We identified the PI3K/mTOR and HIF/VEGF pathways - important in the biology of OCCC - for which multiple inhibitors showed activity against OCCC and synergy with BCL-XL inhibition. Our overarching hypothesis is that the PI3K/mTOR and HIF/VEGF pathways represent fundamental therapeutic vulnerabilities in both ARID1A-mutant and -WT OCCC and that inhibition of these pathways will drive apoptosis in OCCC. In Aim 1, we will characterize BAF protein complex in OCCC parental cell lines and isogenic ARID1A-mutant and -WT cell lines to determine the functional impact of ARID1A mutations. We will compare genomic alterations, mRNA expression, and protein expression of members of the PI3K/mTOR, HIF/VEGF, and apoptosis pathways in ARID1A-deficient and -WT OCCC using exome sequencing, transcriptional profiling, and protein profiling in cell lines and patient samples. In Aim 2, we will study targeted therapies against the PI3K/mTOR and HIF/VEGF pathways in ARID1A-mutant and -WT OCCC to identify the most active compounds, and will evaluate combinations of inhibitors of each pathway together or combined with DT2216, a novel BCL-XL degrader. We will nominate clinically relevant therapeutic strategies effective in both ARID1A-mutant and -WT OCCC. In Aim 3, we will test the most promising compounds in clinically relevant OCCC models. We will evaluate novel therapies in existing and newly developed OCCC patient-derived organoids. For in vivo validation, we will test PI3K/mTOR and HIF/VEGF inhibitors alone and combined with each other and with DT2216 in OCCC cell line xenografts. We will also use a novel implantable microdevice technology that evaluates responses to multiple drugs in tumors to efficiently validate combinations of candidate therapeutics and DT2216. In vivo models are critical for evaluating these pathways in solid tumors due to the impact of the tumor microenvironment on hypoxia and other factors affecting PI3K/mTOR and HIF/VEGF signaling, and for the microdevice approach which requires implantation into solid tumors. I aim to leverage my experience in laboratory and translational research, expert collaborators, and innovative technologies, to identify and validate new targeted agents for the treatment of OCCC. This project will promote the National Cancer Institute’s mission by developing new treatments for an aggressive subtype of ovarian cancer and build resources and technologies to advance ovarian cancer research.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $528,099 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Treatment Research	000	1	8/20/2026	NEW	$528,099
														Subtotal = $528,099

Grand Total All Awards = $528,099

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Therapeutic vulnerabilities of ARID1A-mutant and -wildtype ovarian clear cell carcinoma

Award Number: R01CA307360

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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