# Identifying metabolic dependencies in Hurthle cell carcinoma of the thyroid-Res 1

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $503,309

## Abstract

Project Summary:
Cancers require metabolic adaptations to support the unbridled proliferation that drives tumor growth. Mutations
in the mitochondrial genome (mtDNA) are observed in many cancers, but the role of these mutations in shaping
cellular metabolism and tumor growth is incompletely understood. mtDNA mutations that impair components of
the electron transport chain (ETC) appear to be selected against in most forms of cancer. Hürthle cell carcinoma
of the thyroid (HTC) is clinically aggressive cancer uniquely enriched for loss-of-function mtDNA mutations in
components of complex I of the ETC. We propose that HTC represents an ideal disease outlier in which to
interrogate the role of mtDNA alterations and ETC function in cancer. In this proposal, we employ unique and
highly complementary approaches to characterize the metabolic impact of mtDNA mutations in HTC and other
forms of thyroid and kidney cancer. First, we have developed a clinical protocol to monitor central carbon directly
in surgical patients using stable isotope tracing (Aim 1). Second, we have identified a synthetic lethal interaction
encoded by complex I mutation and identified a promising small molecule therapeutic using patient-derived
models (Aim 2). Finally, we have developed novel GEMMs from which to interrogate the role of complex I
function in thyroid tumorigenesis (Aim 3). These approaches are highly complementary and synergistic, yet
each is independently poised to bridge key knowledge gaps and lead to new insights into metabolic regulation
in cancer. The overall goals of this proposal are to characterize the metabolic adaptations necessitated by
complex I loss in HTC directly in patients undergoing thyroid surgery, to identify and target metabolic liabilities
as a result of metabolic re-wiring downstream of complex I loss, and to determine whether complex I loss acts
to promote or alter thyroid tumor formation in mice. These findings will be of immediate and direct relevance to
thyroid cancer patients, provide new insights relevant to other tumors harboring mtDNA mutations and have
broad implications across cancer types by providing new insights into ETC function in cancer.

## Key facts

- **NIH application ID:** 10894805
- **Project number:** 5R01CA276527-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** David Glenn McFadden
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $503,309
- **Award type:** 5
- **Project period:** 2023-07-27 → 2028-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10894805

## Citation

> US National Institutes of Health, RePORTER application 10894805, Identifying metabolic dependencies in Hurthle cell carcinoma of the thyroid-Res 1 (5R01CA276527-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10894805. Licensed CC0.

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