Drugs Against Alpha-Ketoglutarate May Combat Deadly Childhood Brain Tumor

Summary: Experimental drugs designed to reduce the body’s natural production of alpha-ketoglutarate slow tumor growth and increase lifespan in mouse models of DIPG.


Every year, 150 to 300 children in the United States are diagnosed with diffuse intrinsic pontine gliomas (DIPGs), aggressive and lethal tumors that grow deep inside the brain, for which there are no cures. In a study funded by the National Institutes of Health, researchers showed that experimental drugs designed to lower the body’s natural production of alpha-ketoglutarate extended the lives of mice harboring DIPG tumors by slowing the growth of the cancer cells. Interestingly, they also found that artificially raising alpha-ketoglutarate levels with DIPG-causing genes may slow the growth of other brain tumors. The results, published in Cancer Cell, were part of a nationwide study that explored the cyclical role that cancer cell metabolism may play in regulating brain tumor genes.

Led by senior author Sriram Venneti, M.D., Ph.D., and a team of researchers at the University of Michigan Medical School in Ann Arbor, the researchers primarily studied H3K27M tumors, DIPGs linked to mutations in a gene, called histone 3. Histones are proteins cells spool chromosomes around. This helps cells cram lengthy chromosomes into tiny nuclei and control gene activity. Any genes that are buried in the spools cannot be read and are thus turned off. Cells can “epigenetically” fine tune spooling by using a process known as methylation to chemically tag histones. For years scientists knew that cancer genes often alter the metabolism of tumors. In this study, the researchers not only found that this may be true for patients with H3K27M tumors but also that these alterations in metabolism may be part of a feedback loop involving alpha-ketoglutarate (α-KG), that epigenetically keeps these and other brain tumors in a cancerous state.

This shows a brain scan
Brains scans helped NIH funded researchers find that manipulating cancer cell metabolism may combat diffuse intrinsic pontine gliomas (DIPGs) and other brain tumors. Above is a scan of a DIPG patient. Image is credited to Venneti lab, University of Michigan Medical School, Ann Arbor.

Brain scans of H3K27M patients showed that they had higher levels of certain precursor metabolites – namely glucose and glutamine – than patients with deep brain tumors who do not carry the H3K27M mutations. Then through a series of detailed experiments on mice and cells in petri dishes, the researchers found that H3K27M mutations induced the cancer cells to produce high levels of α-KG and this, in turn, spurred more growth. Further results suggested that this happened because α-KG prevented methylation of histones and thus epigenetically kept genes that are vital for cancer cells exposed and active. For instance, lowering α-KG levels with experimental drugs increased histone methylation, slowed cancer cell growth, and helped mice harboring the DIPG tumors live longer. In contrast, they saw surprisingly opposite results in lower grade tumors associated with mutations in isocitrate dehydrogenase genes (IDH1), which naturally produce lower levels of α-KG. Introducing H3K237M genes into IDH1 tumors slowed growth by raising alpha-ketoglutarate levels which, in turn, increased methylation and turned off cancer-sustaining genes. The researchers concluded that understanding the intricate details behind these feedback loops may help researchers devise effective ways to treat DIPG and other brain tumors.

Funding: This study was supported by the NIH (NS110572, NS099427), the Chad Tough Foundation, Mathew Larson Foundation, St. Baldrick’s Foundation, Claire McKenna Foundation, Alex’s Lemonade Stand Foundation for Childhood Cancer, Storm the Heavens Foundation, a joint Chad Tough Foundation and Michael Mosier Defeat DIPG Foundation fellowship award, the Sidney Kimmel Foundation, Doris Duke Foundation, Sontag Foundation, the Toyota Research Institute, Rudi Schulte Research Institute, and the Ian’s Friends Foundation.

About this brain cancer research article

Christopher G. Thomas – NIH/NINDS
Image Source:
The image is credited to Venneti lab, University of Michigan Medical School, Ann Arbor.

Original Research: Closed access
“Integrated Metabolic and Epigenomic Reprogramming by H3K27M Mutations in Diffuse Intrinsic Pontine Glioma” by Chung, C. et al. Cancer Cell.


Integrated Metabolic and Epigenomic Reprogramming by H3K27M Mutations in Diffuse Intrinsic Pontine Glioma

H3K27M diffuse intrinsic pontine gliomas (DIPGs) are fatal and lack treatments. They mainly harbor H3.3K27M mutations resulting in H3K27me3 reduction. Integrated analysis in H3.3K27M cells, tumors, and in vivo imaging in patients showed enhanced glycolysis, glutaminolysis, and tricarboxylic acid cycle metabolism with high alpha-ketoglutarate (α-KG) production. Glucose and/or glutamine-derived α-KG maintained low H3K27me3 in H3.3K27M cells, and inhibition of key enzymes in glycolysis or glutaminolysis increased H3K27me3, altered chromatin accessibility, and prolonged survival in animal models. Previous studies have shown that mutant isocitrate-dehydrogenase (mIDH)1/2 glioma cells convert α-KG to D-2-hydroxyglutarate (D-2HG) to increase H3K27me3. Here, we show that H3K27M and IDH1 mutations are mutually exclusive and experimentally synthetic lethal. Overall, we demonstrate that H3.3K27M and mIDH1 hijack a conserved and critical metabolic pathway in opposing ways to maintain their preferred epigenetic state. Consequently, interruption of this metabolic/epigenetic pathway showed potent efficacy in preclinical models, suggesting key therapeutic targets for much needed treatments.

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