Drugs designed to lower alpha-ketoglutarate levels could help fight DIPG tumors

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.

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.

Source:
Journal reference:

Chung, C., et al. (2020) Integrated Metabolic and Epigenomic Reprograming by H3K27M Mutations in Diffuse Intrinsic Pontine Gliomas. Cancer Cell. doi.org/10.1016/j.ccell.2020.07.008.

Comments

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of AZoLifeSciences.
Post a new comment
Post
Azthena logo

AZoM.com powered by Azthena AI

Your AI Assistant finding answers from trusted AZoM content

Your AI Powered Scientific Assistant

Hi, I'm Azthena, you can trust me to find commercial scientific answers from AZoNetwork.com.

A few things you need to know before we start. Please read and accept to continue.

  • Use of “Azthena” is subject to the terms and conditions of use as set out by OpenAI.
  • Content provided on any AZoNetwork sites are subject to the site Terms & Conditions and Privacy Policy.
  • Large Language Models can make mistakes. Consider checking important information.

Great. Ask your question.

While we only use edited and approved content for Azthena answers, it may on occasions provide incorrect responses. Please confirm any data provided with the related suppliers or authors. We do not provide medical advice, if you search for medical information you must always consult a medical professional before acting on any information provided.

Your questions, but not your email details will be shared with OpenAI and retained for 30 days in accordance with their privacy principles.

Please do not ask questions that use sensitive or confidential information.

Read the full Terms & Conditions.

You might also like...
A New AI Model that can Distinguish Between Male and Female Brain Activity