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."
Cahill is an associate professor of Neurosurgery, and Wakimoto is an assistant professor of Neurosurgery at Harvard Medical School. The co-senior author of the Cancer Cell paper is Andrew Chi, MD, formerly of the MGH Cancer Center and Department of Neurology and now at the Perlmutter Cancer Center at the NYU Langone Medical Center. Kensuke Tateishi, MD, MGH Neurosurgery, is the paper's lead author.
Additional co-authors are A. John Iafrate, MD, PhD, Shota Tanaka, MD, Franziska Loebel, MD, Nina Lelic, Robert E. Gerszten, MD, Yiyun Zhang, MD, Jing-Ruey J. Yeh, PhD, William T. Curry, MD, Dan Zhao, MD, PhD, Sudhandra Sundaram, Fares Nigim, MD, Mara V. A. Koerner, Quan Ho, David E. Fisher, MD, PhD, Elisabeth M. Roider, MD, Lajos V. Kemeny, PhD, Keith T. Flaherty, MD, and Tracy T. Batchelor, MD -- all at MGH. Additionally involved were Dmitri Wiederschain, PhD, Olivier Bedel, PhD, Gejing Deng, PhD, Bailin Zhang, PhD, and Timothy He, PhD, Sanofi Oncology, and Yardena Samuels, PhD, Weizmann Institute of Science, Rehovot, Israel.
Support for the study was provided by the National Cancer Institute, the Burroughs Wellcome Fund, the Society for Nuclear Medicine and Molecular Imaging Wagner-Torizuka Fellowship, the Japan Foundation, and the KANAE foundation.
Massachusetts General Hospital, founded in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $760 million and major research centers in AIDS, cardiovascular research, cancer, computational and integrative biology, cutaneous biology, human genetics, medical imaging, neurodegenerative disorders, regenerative medicine, reproductive biology, systems biology, transplantation biology and photomedicine. In July 2015, MGH returned into the number one spot on the 2015-16 U.S. News & World Report list of "America's Best Hospitals."