# Metabolic vulnerabilities in cancers with impaired TCA cycle activity

> **NIH NIH F30** · WEILL MEDICAL COLL OF CORNELL UNIV · 2024 · $53,994

## Abstract

PROJECT SUMMARY
Cancer cells exploit multiple metabolic strategies to generate biosynthetic precursors that fuel malignant
proliferation. Such metabolic redundancy and plasticity hampers effectiveness of therapies that target cancer
cell metabolism and underscores the importance of identifying tumor types most likely to respond to metabolic
inhibitors. The goal of this proposal is to test the hypothesis that tumors with impaired metabolic pathways will
have limited metabolic plasticity in generating critical biosynthetic intermediates, rendering them susceptible to
metabolic inhibition. We focus on the tricarboxylic acid (TCA) cycle, which is a central metabolic hub that
supports cell growth and yet is truncated or impaired in several forms of human renal cell cancer (RCC). A
subset of RCC tumors arise from germline deficiencies in core TCA cycle enzymes succinate dehydrogenase
(SDH) or fumarate hydratase (FH); more commonly, RCC tumors have hyperactive hypoxia-inducible factor
(HIF) signaling that blunts TCA cycle metabolism. The goal of this proposal is to determine whether these
RCC tumors with altered TCA cycle activity are dependent upon ATP citrate lyase (ACL) as an
alternative source of critical metabolic intermediates. Aspartate, synthesized from TCA cycle intermediate
oxaloacetate, supports nucleotide and protein synthesis and has emerged as a critical limitation for tumor
growth. Nevertheless, how tumors with impaired TCA cycle flux sustain aspartate generation—and whether
these compensatory pathways represent a targetable liability—remains largely unknown. My preliminary data
demonstrate that SDH/FH-deficient or HIF-active RCC cells have reduced aspartate pools relative to their
isogenic controls and that ACL inhibition selectively impairs survival of these cells with defective TCA cycle
metabolism. In Aim 1, I will leverage a panel of isogenic RCC lines to test whether genetic and pharmacologic
ACL inhibition specifically impairs growth of SDH-/FH-deficient RCC cells in vitro and in vivo. I will exploit
genetic tools that supply intracellular aspartate to test the hypothesis that aspartate provision underlies the
ACL requirement in SDH-/FH-deficient cells. In Aim 2, I will use RCC cells with hyperactive HIF driven by loss
of the von Hippel Lindau tumor suppressor to determine whether cells with suppressed oxidative TCA cycle
activity depend on ACL to produce aspartate and enable growth in vitro and in vivo. These studies will shed
light not only on a potential metabolic Achilles heel in SDH-/FH-/VHL-null tumors but will also serve as proof of
principle that cancer cells with TCA cycle dysfunction engage ACL as an alternative route of synthesizing
anabolic precursors. The work and training plan outlined in this proposal will be completed in the laboratory of
Dr. Lydia Finley with the co-advisement of Dr. Ross Levine at Memorial Sloan Kettering Cancer Center and will
ideally prepare the applicant for further clinical training and a care...

## Key facts

- **NIH application ID:** 10975852
- **Project number:** 5F30CA284711-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Abigail Xie
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $53,994
- **Award type:** 5
- **Project period:** 2023-08-15 → 2027-08-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10975852

## Citation

> US National Institutes of Health, RePORTER application 10975852, Metabolic vulnerabilities in cancers with impaired TCA cycle activity (5F30CA284711-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10975852. Licensed CC0.

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