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Reprogramming the Tumor Microenvironment in Ovarian Cancer

Award Number: R01CA254342
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Reprogramming the Tumor Microenvironment in Ovarian Cancer - PROJECT SUMMARY High-grade serous ovarian cancer (HGSOC) is the leading cause of death from gynecologic malignancies. Most patients initially respond to chemotherapy after surgery, yet ~80% will recur with disease that becomes resistant to treatment. Immune therapies have shown great promise, but with limited efficacy in HGSOC. The HGSOC tumor microenvironment (TME) is highly immuno-suppressive and this is hypothesized to promote tumor immune evasion. We have developed two new implantable syngeneic mouse ovarian tumor models that will allow for the molecular analysis of tumor- and host-specific signals driving immune evasion. By selecting for aggressive growth in mice, we have extensively characterized KMF cells (gains in genes for KRas, Myc, and FAK) that exhibit many phenotypic similarities to HGSOC; intrinsic chemo-resistance and potent immune suppression. We will focus on FAK (focal adhesion kinase), a tyrosine kinase canonically supporting cell motility signaling. FAK is the fifth highest amplified gene in HGSOC and greater than 65% of patients exhibit elevated FAK mRNA with poor prognostic significance. Using pharmacological FAK inhibitors, FAK knockout, FAK re-expression, complementation, and bioinformatic analyses of KMF cells in tumor-bearing mice, we find that FAK drives the expression of a select group of cytokines and tumor-associated surface proteins involved in regulating tumor growth and immune evasion. Inhibiting FAK results in decreased myeloid-derived suppressor cell (MDSC) recruitment, increased CD4 and CD8 T cell tumor infiltration, and decreased expression of PD-L1, CD112, and CD155 checkpoint regulatory proteins on KMF cells in vivo. These changes are consistent with a normalization or reprogramming of the ovarian TME by FAK inhibition in a tumor-intrinsic manner. FAK inhibition also prevents bloody ascites formation in the KMF model. A second newly-developed T antigen-driven FAK floxed mouse ovarian carcinoma model (MOVCAR) revealed that FAK loss prevents tumor growth in syngeneic low-T mice. FAK-null MOVCAR tumors were infiltrated by CD45+ leukocytes, and when evaluated in immune-deficient mice, orthotopic FAK-null MOVCAR tumor growth was enhanced. This proposal will test the hypothesis that tumor-intrinsic FAK activation facilitates immune-suppressive related changes to the TME. Aim-1 will use a new inducible FAK expression system to evaluate FAK nuclear localization- and kinase-dependent signals driving malignancy, chemokine expression, and MDSC recruitment. Aim-2 will test the role CD112/CD155 immune checkpoint protein expression and whether FAK inhibition may combine with antibodies to TIGIT (T cell immunoreceptor with Ig and ITIM domains) to limit tumor growth via effects on T cells. Aim-3 will use an inducible knockout of FAK, of the related Pyk2 kinase (new model), or inducible expression of kinase-inactive FAK in mouse endothelial cells, with the KMF implantable tumor model, to test stromal FAK and Pyk2 signaling on the TME. These mouse studies, with analyses of patient tumors, will provide important insights on the role of FAK inhibition to enhance immunotherapy efficacy for HGSOC.


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 = $0 )
2026	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	5	11/26/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $392,449 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	5	6/26/2024	NON-COMPETING CONTINUATION	$392,449
														Subtotal = $392,449

Issue Date FY: 2023 ( Subtotal = $404,843 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	4	6/20/2023	NON-COMPETING CONTINUATION	$404,843
														Subtotal = $404,843

Issue Date FY: 2022 ( Subtotal = $404,843 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	3	6/27/2022	NON-COMPETING CONTINUATION	$404,843
														Subtotal = $404,843

Issue Date FY: 2021 ( Subtotal = $413,104 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	2	7/28/2021	NON-COMPETING CONTINUATION	$413,104
														Subtotal = $413,104

Issue Date FY: 2020 ( Subtotal = $443,654 )
2020	2020	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Biology Research	000	1	7/3/2020	NEW	$443,654
														Subtotal = $443,654

Grand Total All Awards = $2,058,893

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Reprogramming the Tumor Microenvironment in Ovarian Cancer

Award Number: R01CA254342

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/03/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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