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Identifying Immune Mediators in BRCA1/2 Deficient High Grade Serous Ovarian Cancer

Award Number: F31CA310488
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2029

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Identifying Immune Mediators in BRCA1/2 Deficient High Grade Serous Ovarian Cancer - Project Summary/Abstract High grade serous ovarian cancer (HGSOC) is characterized by high genomic instability where roughly 50% have deficiency in homologous recombination (HR) due to mutations in BRCA1 and BRCA2. Poly (ADP-ribose) polymerase inhibition (PARPi) is the standard for maintenance therapy for HR deficient cancers such as HGSOC. Interestingly, HGSOC tumors have chronic elevation of type 1 interferon signaling. Type 1 interferon (IFN) signaling is a critical immune mediating pathway that when acutely activated by strategies such as PARPi promotes an anti-tumor immune response in murine models. However, HGSOC and other cancers with genome instability associate with poor responses or resistance to immunotherapies and have immune suppressive tumor microenvironments (TME). Clinical trials that combine PARPi and immunotherapy had low response rates. The mechanism driving this immune suppression and tumor progression is unknown. The goal of this study is to identify the immune cells and immune signaling mediators that drive an immune suppressive TME and promote BRCA deficient HGSOC tumor progression. To address the relationship between BRCA deficiency, high inflammatory signaling, and an immune suppressive TME, I have generated novel, syngeneic BRCA deficient HGSOC murine cell line models to allow analyses in immune competent hosts. My preliminary data demonstrates that abolishment of type 1 IFN signaling in BRCA2 deficient HGSOC tumors does not affect tumor progression and survival of mice, suggesting possible alternative immune mediating pathways driving tumor progression and immune suppression. Interestingly, I observe increased activity of the inflammasome, a multimeric protein complex that promotes pro-inflammatory cytokine release. Loss of caspase-1, the major inflammasome effector, in BRCA2 deficient HGSOC tumors prolonged survival of mice. Thus, I hypothesize that genomic instability and DNA damage due to BRCA deficiency activates the inflammasome in HGSOC that mediates the immune response towards an immune suppressive, pro-tumor TME. With our novel, syngeneic BRCA deficient HGSOC models, I am uniquely positioned to Aim 1: Determine the mechanism of inflammasome activation in BRCA deficient HGSOC tumors and Aim 2: Identify the immune cells and tumor cell intrinsic mediators driving BRCA deficiency associated TME inflammation and determine their roles in immune suppression in HGSOC tumors. In Aim 1, I will determine the conditions necessary for inflammasome activation: amount of DNA damage, duration of DNA damage in the cells, presence of cytoplasmic DNA or DNA damage signaling activity. In Aim 2, I will determine the immune cell mediators, by immunofluorescence, and which effectors of the inflammasome, by genetic knockout of each one, drives an immune suppressive TME and tumor progression. Additionally, I will test how loss of each inflammasome effector impacts HGSOC tumor sensitivity to PARPi and immunotherapies alone or in combination. Completion of these aims may inform predictive biomarkers and therapeutic targets to improve HGSOC responses to immunotherapies and patient outcomes.


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 = $50,114 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	001	1	4/6/2026	NEW	$0
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	4/6/2026	NEW	$50,114
														Subtotal = $50,114

Grand Total All Awards = $50,114

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Identifying Immune Mediators in BRCA1/2 Deficient High Grade Serous Ovarian Cancer

Award Number: F31CA310488

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2029

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