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Targeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision Therapies for Uveal Melanoma

Award Number: R01CA257505
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Targeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision Therapies for Uveal Melanoma - Targeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision Therapies for Uveal Melanoma G protein-coupled receptors (GPCRs) represent the largest family of cell surface proteins involved in signal transmission. GPCRs play key physiological roles and their dysfunction contributes to some of the most prevalent human diseases, making them the target of >25% of all therapeutic drugs. Strikingly, our recent analysis of human cancer genomes revealed an unanticipated high frequency of mutations in G proteins and GPCRs in most tumor types. Indeed, nearly 30% of human cancers harbor mutations in GPCRs or G proteins. While their tumorigenic potential is under investigation, activating mutations in GNAQ and GNA11 (herein referred as GNAQ oncogenes, which encode GTPase deficient and constitutively active Gαq proteins), were identified in ~93% of uveal melanoma (UM) and 4% of skin cutaneous melanoma (SKCM), respectively, where they act as oncogenic drivers. UM is the most common primary cancer of the eye in adults, affecting more than 2,500 patients each year in the US alone, nearly 50% of which will die from liver metastasis. To date, there are no effective therapeutic options to treat metastatic UM disease (mUM). We recently demonstrated that YAP activation is central to UM growth and uncovered a novel direct link between Gαq-FAK driven tyrosine phosphorylation networks and YAP activation. Our central hypothesis is that this signaling specificity may represent a systems vulnerability that can be exploited for the development of new precision therapies for mUM. Our overall hypothesis is that our proposed studies targeting FAK, which acts downstream from Gαq, and its compensatory (resistance) or synthetic lethal (sensitizing) mechanisms will provide an oncogene-specific therapeutic approach for advanced and mUM, resulting in increased antitumor activity with lower toxicities and fewer side effects. Ultimately, our premise is that FAK is an integral part of the GNAQ oncogenic pathway and that in turn, FAK blockade with clinically relevant FAK inhibitors (FAKi) may represent a precision therapeutic approach for the treatment of mUM, alone or as part or as part of novel signal transduction-based precision co-targeting strategies. This will be investigated in 3 aims: Aim 1: To exploit GNAQ-synthetic lethal and gene interaction networks to expose systems vulnerabilities resulting in UM cell death as a precision therapeutic approach to treat mUM. Aim 2. To establish the therapeutic potential of co-targeting the Gαq-FAK regulated pathway in vivo. Aim 3. Characterization of FAKi/MEKi tolerant persister populations and mechanisms of acquired resistance


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: 2025 ( Subtotal = $469,899 )
2025	2025	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	5	3/6/2025	NON-COMPETING CONTINUATION	$469,899
														Subtotal = $469,899

Issue Date FY: 2024 ( Subtotal = $502,859 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	4	5/24/2024	NON-COMPETING CONTINUATION	$502,859
														Subtotal = $502,859

Issue Date FY: 2023 ( Subtotal = $525,822 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	3	3/21/2023	NON-COMPETING CONTINUATION	$525,822
														Subtotal = $525,822

Issue Date FY: 2022 ( Subtotal = $535,362 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	001	2	5/9/2022	NON-COMPETING CONTINUATION	$43,706
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	2	3/16/2022	NON-COMPETING CONTINUATION	$491,656
														Subtotal = $535,362

Issue Date FY: 2021 ( Subtotal = $565,730 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	001	1	5/28/2021	NEW	$86,026
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cancer Treatment Research	000	1	3/10/2021	NEW	$479,704
														Subtotal = $565,730

Grand Total All Awards = $2,599,672

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Targeting Systems Vulnerabilities in the Gαq/GNAQ Oncogenic Signaling Circuitry: New Precision Therapies for Uveal Melanoma

Award Number: R01CA257505

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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