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Targeting purine salvage dependency for disease control in FH-deficient renal cell carcinoma

Award Number: F30CA310543
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 08/01/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2029

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Targeting purine salvage dependency for disease control in FH-deficient renal cell carcinoma - ABSTRACT Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a highly penetrant, aggressive cancer syndrome caused by germline mutations in fumarate hydratase (FH), an enzyme of the tricarboxylic acid cycle. Individuals with FH-deficiency develop early-onset, rapidly metastasizing kidney tumors with few effective treatment options and no targeted therapies. The long-term objective of this proposal is to define the molecular and metabolic mechanisms driving HLRCC tumorigenesis and leverage these insights to develop novel, sustainable therapeutic strategies for controlling disease initiation and progression. Recent work from the Christofk laboratory has identified a fixed dependency on purine salvage in FH-deficient cells, implicating this pathway as a promising metabolic vulnerability to target. This project pursues two specific aims: (1) elucidate the genetic and metabolic drivers of HLRCC tumor initiation and progression using patient-informed combinatorial gene knockouts in vitro and in vivo, and (2) evaluate dietary purine restriction as a targeted therapeutic intervention. A novel, kidney-specific, Cre-mediated FH-deficient mouse model will be developed to better recapitulate the stochastic nature of tumor initiation observed in patients. Multi-omics profiling, CRISPR-based transformation studies, and in vivo purine restriction regimens will be employed to map tumorigenic pathways and assess therapeutic efficacy. Metabolite profiling and isotope tracing will be used to monitor metabolic reprogramming in tumor and healthy tissues in response to disease initiation and response to dietary purine restriction. The proposed research will be conducted in the Christofk Lab at UCLA, an environment uniquely positioned at the intersection of basic biochemistry, metabolism, and translational oncology. The fellowship training plan includes formal mentorship in metabolomics, translational modeling, and biochemical assay design, as well as ongoing collaboration with clinical departments. Furthermore, the proximity and access to patient-care activities at UCLA Health the Jonsson Comprehensive Cancer Center will facilitate longitudinal clinical exposure and tandem patient care and basic scientific educational activities. This project will provide rigorous, multidisciplinary training to prepare for a career in academic surgery and translational research. Ultimately, this work seeks to advance mechanistic understanding of HLRCC pathogenesis while establishing a sustainable, non-pharmacologic therapeutic strategy applicable to this and potentially other metabolically dysregulated cancers.


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 = $43,058 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	000	1	7/20/2026	NEW	$43,058
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Research Manpower	001	1	7/20/2026	NEW	$0
														Subtotal = $43,058

Grand Total All Awards = $43,058

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Targeting purine salvage dependency for disease control in FH-deficient renal cell carcinoma

Award Number: F30CA310543

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 08/01/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2029

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