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Potential treatment target for IDH1-mutant cancers identified

Tumors driven by mutation in metabolic enzyme are vulnerable to depletion of metabolite NAD+

Date:
December 14, 2015
Source:
Massachusetts General Hospital
Summary:
A potential new treatment target for tumors -- including a significant percentage of malignant brain tumors -- driven by mutations in an important metabolic enzyme has been identified by a group of researchers.
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A Massachusetts General Hospital (MGH)-based research team has identified a potential new treatment target for tumors -- including a significant percentage of malignant brain tumors -- driven by mutations in an important metabolic enzyme. In their report in the Dec. 14 issue of Cancer Cell, the investigators describe finding, in cellular and animal models, that tumors characterized by IDH1 mutations are greatly susceptible to depletion of NAD+, a critical metabolic cofactor.

"Targeting the basic changes in cancer metabolism can offer new treatment approaches for patients. Our finding that IDH1-mutant cancer cells are dependent on NAD+ supports the proposal that medications that can decrease levels of this metabolite, which are in development, have the potential to specifically treat these cancers," says Daniel Cahill, MD, PhD, of the Pappas Center for Neuro-Oncology in the MGH Cancer Center and the MGH Department of Neurosurgery, co-senior author of the Cancer Cell paper.

IDH1 and a related enzyme called IDH2 play essential roles in cellular metabolism, including the processes by which cells convert glucose and other nutrients into the molecule ATP, providing the energy needed for cellular survival. In 2008 it was discovered that IDH1 mutations are involved in several types of cancers. The gene is mutated in around 20 percent of adult gliomas, particularly in tumors appearing in young adult patients, in more than 10 percent of acute myeloid leukemias and in a smaller percentage of other cancers.

One clear result of IDH1 mutation is a 100-fold elevation in levels of the metabolite 2-HG, which is known to mediate several properties that lead to tumor development, and drugs that decrease levels of 2-HG are currently under development. To find additional ways of blocking the mutation's effects, the MGH-based team used an agent that inhibits the activity of the mutated enzyme to look into whether other metabolic pathways might be altered in IDH1-mutant cells. They were surprised to find that, while inhibiting the activity of the mutated enzyme in tumor cells reduced 2-HG levels, in many cases that reduction did not halt cell growth. Detailed metabolic profiling of IDH1-mutant cells revealed that inhibiting the mutated enzyme greatly increased levels of NAD+, a cofactor that plays a role in several cellular energy processes. Additional experiments found that depletion of NAD+ induced the death of IDH1-mutant tumor cells and inhibited tumor growth in an animal model of glioma.

"Accumulation of excess 2-HG is known to drive several changes leading to tumor development, but our results indicate that simply depleting 2-HG levels was not sufficient to halt the growth of several types of later-stage IDH1-mutant tumors," says co-author Hiroaki Wakimoto, MD, PhD, director of the Brain Tumor Stem Cell Laboratory in the MGH Cancer Center and the MGH Department of Neurosurgery. "In addition, we found that mutant IDH1 reduces expression of an enzyme that maintains NAD+ levels, rendering IDH1-mutant tumor cells highly sensitive to direct NAD+ depletion. Several drugs that inhibit the synthesis of NAD+ are already in clinical trials, and these agents may prove useful for patients with IDH-mutant cancers. While we primarily focused on IDH1-mutant gliomas, we also found evidence that NAD+ inhibition could slow the growth of other types of cancer with this mutation."


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Materials provided by Massachusetts General Hospital. Note: Content may be edited for style and length.


Journal Reference:

  1. Kensuke Tateishi, Hiroaki Wakimoto, A. John Iafrate, Shota Tanaka, Franziska Loebel, Nina Lelic, Dmitri Wiederschain, Olivier Bedel, Gejing Deng, Bailin Zhang, Timothy He, Xu Shi, Robert E. Gerszten, Yiyun Zhang, Jing-Ruey J. Yeh, William T. Curry, Dan Zhao, Sudhandra Sundaram, Fares Nigim, Mara V.A. Koerner, Quan Ho, David E. Fisher, Elisabeth M. Roider, Lajos V. Kemeny, Yardena Samuels, Keith T. Flaherty, Tracy T. Batchelor, Andrew S. Chi, Daniel P. Cahill. Extreme Vulnerability of IDH1 Mutant Cancers to NAD Depletion. Cancer Cell, 2015; 28 (6): 773 DOI: 10.1016/j.ccell.2015.11.006

Cite This Page:

Massachusetts General Hospital. "Potential treatment target for IDH1-mutant cancers identified." ScienceDaily. ScienceDaily, 14 December 2015. <www.sciencedaily.com/releases/2015/12/151214130033.htm>.
Massachusetts General Hospital. (2015, December 14). Potential treatment target for IDH1-mutant cancers identified. ScienceDaily. Retrieved March 28, 2024 from www.sciencedaily.com/releases/2015/12/151214130033.htm
Massachusetts General Hospital. "Potential treatment target for IDH1-mutant cancers identified." ScienceDaily. www.sciencedaily.com/releases/2015/12/151214130033.htm (accessed March 28, 2024).

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