# Targeting Nicotinamide Adenine Dinucleotide (NAD+) metabolism in IDH mutant gliomas

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $480,143

## Abstract

Diffuse gliomas are a leading cause of cancer-related death in people under 45 years
old, with malignant brain tumors resulting in the greatest number of years of potential life lost in
US adults. Modern large-scale genetic discovery has identified somatic molecular genomic
alterations that can better classify these tumors. Recurrent isocitrate dehydrogenase (IDH) gene
mutations are found in up to 20% of adult diffuse gliomas, identifying tumors with distinct
etiology, associated genetic alterations, and overall natural history. As a result, IDH mutant
gliomas have been newly-recognized as separate diagnostic entities within the 2016 World
Health Organization Histological Classification. These gliomas are typically diagnosed in
younger adults ranging from 20-50 years old, initially presenting as lower-grade lesions that can
be responsive to standard-of-care treatments such as surgical resection, radiation and
chemotherapy. However, these cancers inexorably progress to become higher-grade lesions,
and prove fatal in most cases. New treatments are needed.
 In our prior work, we have shown that the altered metabolism within IDH1 mutant cells
exposes the nicotinamide adenine dinucleotide (NAD+) biosynthetic enzyme nicotinamide
phosphoribosyltransferase (NAMPT) to selective inhibition with small molecules, resulting in
profound genotype-specific metabolic vulnerabilities in IDH1 mutant cancer cells. Highlighting
the central importance of NAD+ levels in IDH mutant gliomas, these observations strongly
suggest that alternative strategies targeting NAD+ homeostasis may achieve substantial
efficacy against these tumors. Herein, we propose to evaluate modulation of NAD+ steady-state
levels in IDH mutant gliomas by multiple non-overlapping approaches, to identify unique
dependencies, mediators of sensitivity and potential combinatorial therapeutic strategies. In
addition, we plan to test innovative delivery methods which could minimize the toxicities
associated with NAMPTi monotherapy, widening the therapeutic window for clinical translation.
 The successful completion of our proposed research will open new avenues for targeting
the unique metabolic vulnerabilities of IDH1 mutant gliomas, translating into potential clinical
therapies for patients with these tumors.

## Key facts

- **NIH application ID:** 10114237
- **Project number:** 5R01CA227821-04
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Daniel P. Cahill
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $480,143
- **Award type:** 5
- **Project period:** 2018-03-15 → 2023-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10114237

## Citation

> US National Institutes of Health, RePORTER application 10114237, Targeting Nicotinamide Adenine Dinucleotide (NAD+) metabolism in IDH mutant gliomas (5R01CA227821-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10114237. Licensed CC0.

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