Cancer Research: Attacking Brain Tumors With Epigenetic and Drug Therapy

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mutations

Gene mutations and dysregulated processes cause cancer. Image by the National Cancer Institute

The struggle to conquer Cancer continues. Cancer is a deadly disease that strikes locally at first, then slowly usurps the processes of healthy normal cells, for its survival and progression, and eventually uproots the entire being.

Since cancer is a disease of multi-dysregulated processes, researchers should consider innovative approaches like attacking cancer cells using different strategies. In fact, some scientists have already tested multi-therapy approaches and proven that they are beneficial for several diseases – and even some cancers.

Somatic Mutations of Isocitrate Dehydrogenase 1

Gliomas, or brain tumors that arise from the glial cells of astrocytes and oligodendroglia, represent cancers that could benefit from a multi-targeted therapy. The disease progresses from primary benign gliomas to malignant WHO grade IV glioblastoma. The culprit here, is the enzyme, isocitrate dehydrogenase (IDH1/2) that we see frequently mutated in 70% of WHO grade II-III tumors.

The isocitrate dehydrogenase enzyme catalyzes the conversion of isocitrate to a-ketoglutarate. When mutated through a single amino acid substitution, the enzyme’s activity is altered such that it produces an onco-metabolite, D-2-hydroxyglutarate (2-HG) from a-ketoglutarate.

In gliomas, the cancer cells utilize this transformed mutant enzyme to turn a traitor to its own system.

Workings of the Mutant Enzyme IDH1

D-2 hydroxyglutarate, normally present in trace amounts, when expressed in high levels confers an advantage to cancer cells. The onco-metabolite, D-2 hydroxyglutarate is structurally similar to a-ketoglurate, so it can compete and prevent the normal action of several enzymes dependent on a-ketoglutarate in cancer.

DNA hypermethylation is an abnormal characteristic associated with the IDH mutated gliomas. The covalent addition of a methyl group on cytosine residues within CG sequences, distributed on specific gene promoters is pivotal to controlled gene expression. When excessive DNA methylation occurs at the promoters of genes in inappropriate contexts, it inhibits gene transcription.

Several DNA methyltransferases (facilitate the transfer of methyl groups from s-adenosyl-methionine to cytosine base) and demethylase (remove methyl group), essential for establishing and maintaining DNA methylation require a-ketoglutarate for their activity and these enzymes are competitively targeted by 2-HG.

Stop the Cancer: Inhibitor Therapy

In a study published earlier this year in Science, researchers developed a chemical inhibitor (AGI-5198) to the mutant IDH1 enzyme and demonstrated that it reduced the growth of gliomas in mice. When the scientists injected the mice with human glioma xenografts, they developed tumors similar to the humans.

The mutant IDH1 inhibitor, when given orally to these mice, impaired tumor growth by ~55%. AGI-5198 was also able to block the growth of tumor cells in petri dishes as well, by ~50%. The authors were able to reverse the effects of the mutant enzyme, by demonstrating the induced expression of genes responsible for gliogenic differentiation.

Click to Read Page Two: Demethylating Drugs and Epigenetic Therapy

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© Copyright 2013 Dheepa Balasubramanian, PhD, All rights Reserved. Written For: Decoded Science

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