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Targeting Oncogenic PKA signaling mechanisms

Award Number: R01CA279997
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2023
PERIOD OF PERFORMANCE END DATE: 11/30/2028

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Targeting Oncogenic PKA signaling mechanisms - ABSTRACT Of the 6,500 known rare diseases, only about 5% have U.S. Food and Drug Administration-approved treatments. In cancer, rare tumors account for approximately 20% of cancer incidence but often lack established therapeutic regimens. Hence, gaining a molecular understanding of rare tumors is key for development of effective therapies. This multi-investigator proposal investigates oncogenic mutations that activate protein kinase A (PKA) to promote defective cell signaling in rare endocrine and hepatic tumors. Targeted therapeutics have transformed care for patients with rare cancers by targeting oncogenic mutations in protein kinases. PKAc-driven cancers are challenging to target in this way because this broad specificity kinase controls myriad physiological processes. Consequently, selective PKAc inhibitors have been relegated to the role of tool compounds rather than clinically viable drugs. Thus, alternative strategies must be developed to treat PKAc-driven cancers. Our preliminary profiling of oncogenic PKAc mutants provide compelling evidence that PKAc engages downstream protein kinase cascades that impact translation in adrenal and hepatic tumors. We also observed increased mRNA translation as an emerging hallmark of these PKAc driven malignancies. These findings have forged a working hypothesis that PKAc-driven cancers can be treated by targeting downstream effectors such the RNA helicase eIF4A rather than globally blocking the catalytic activity of the kinase. Three specific aims will test this transformative premise. 1) Proteomic and transcriptomic profiling of cells expressing oncogenic PKAc variants that underlie Carney complex, Cushing’s adenoma and fibrolamellar carcinoma will elucidate downstream signaling elements that impinge on mRNA translation. 2) Molecular approaches will investigate new properties imparted by the DNAJ-PKAc-chimeric kinase in fibrolamellar carcinoma that may confer resistance to chemically induced apoptosis. 3) Clinically relevant compounds and novel bivalent inhibitors will dissect the mechanism of eIF4A dependence in PKAc-driven malignancies and patient derived (PDX) models of fibrolamellar carcinoma. This proposal not only builds on a solid foundation of PKAc research, but also affords an unparalleled opportunity to discover, develop and validate drug targets for a group of patients in dire need.


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 = $649,945 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	001	2	11/26/2024	SUPPLEMENT FOR EXPANSION	$61,036
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	002	2	5/30/2025	NON-COMPETING CONTINUATION	$58,890
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	000	2	11/25/2024	NON-COMPETING CONTINUATION	$530,019
														Subtotal = $649,945

Issue Date FY: 2024 ( Subtotal = $637,512 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	001	1	8/20/2024	SUPPLEMENT FOR EXPANSION	$20,836
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	1	12/15/2023	NEW	$616,676
														Subtotal = $637,512

Grand Total All Awards = $1,287,457

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Targeting Oncogenic PKA signaling mechanisms

Award Number: R01CA279997

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2023

PERIOD OF PERFORMANCE END DATE: 11/30/2028

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