# Functions of mutant IDH in cholangiocarcinoma

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $620,855

## Abstract

PROJECT SUMMARY
Isocitrate dehydrogenase 1 is the most frequently mutated metabolic gene across all cancers. Among epithelial
malignancies, IDH1 mutations are particularly common in cholangiocarcinoma, a deadly cancer of the liver bile
ducts. These hot-spot mutations generate the oncometabolite, (R)-2-hydroxyglutarate, which inhibits -
ketoglutarate-dependent enzymes, altering epigenetics and metabolism. While pharmacological inhibition of
mutant IDH1 shows efficacy in cholangiocarcinoma, the effects are not durable, and there has been limited
insight into the basis for response and resistance. Recently, by developing mIDH1-driven genetically
engineered mouse models and utilizing patient samples and models, we demonstrated that mIDH1 causes
tumor cells to evade attack by the immune system. We find that inhibitors of mutant IDH1 slow tumor growth by
reverting this immune evasion phenotype, leading to sensitization to immune checkpoint blockade. A major
mechanism of this evasion involves the (R)-2HG-mediated inactivation of the TET2 demethylase, which
prevents the tumor cells from responding to interferon gamma produced by immune cells. The second
mechanism involves limiting the recruitment and activity of cytotoxic T cells, although we have yet to fully
elucidate the associated molecular basis. Based on our extensive new preliminary data, we hypothesize that
IDH1-mediated control of cellular differentiation and of innate immune signaling are potential mediators of this
T cell cross-talk. The present proposal will test this hypothesis and investigate the interplay between T cell
recruitment and the IFN-g-TET2 program in IDH1 inhibitor response and eventual resistance. These studies
will inform the improved treatment of cholangiocarcinoma and potentially the range of other cancer types
harboring IDH mutations.

## Key facts

- **NIH application ID:** 10932410
- **Project number:** 5R01CA280085-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** NABEEL El-BARDEESY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $620,855
- **Award type:** 5
- **Project period:** 2023-09-20 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10932410

## Citation

> US National Institutes of Health, RePORTER application 10932410, Functions of mutant IDH in cholangiocarcinoma (5R01CA280085-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10932410. Licensed CC0.

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