Mutated IDH1 gene has novel enzyme activity consistent with cancer-causing gene: Study

Agios Pharmaceuticals today announced that its scientists have established, for the first time, that the mutated IDH1 gene has a novel enzyme activity consistent with a cancer-causing gene, or oncogene. This breakthrough discovery shows that the mutated form of IDH1 produces a metabolite, 2-hydroxyglutarate (2HG), which may contribute to the formation and malignant progression of gliomas, the most common type of brain cancers. This discovery appears to reverse the previously held belief that IDH1 was non functional for cancer-causing activity. It is also one of the first reported instances where a metabolic enzyme such as IDH1 is shown to play a role in cancer formation, in this case through altered metabolic activity.

This finding creates opportunities for therapeutic intervention in brain cancer and other cancers where IDH1 mutations are present using new drugs that can target the IDH1 metabolic pathway. The Agios research also identified an exciting new biomarker, 2HG, that could be used to develop an important diagnostic. The research was published on November 22 by the journal Nature, in a paper entitled “Cancer-associated IDH1 mutations produce 2-hydroxyglutarate (2HG)”.

“This groundbreaking work is profound for the field,” said Professor Lew Cantley, Ph.D., Director of the Cancer Center at the Beth Israel Deaconess Medical Center, a founder of Agios and a supporting author. “The team at Agios has demonstrated that what was previously considered an inactive enzyme is in reality an active oncogene and a potential therapeutic target. This has fundamentally changed our understanding of the field. Additionally, there is an easily measured metabolic biomarker, 2HG, that will help in the diagnosis and treatment of any related therapeutics that arise from this work.”

Agios scientists uncovered the function of the IDH1 mutation by employing novel techniques in a new area of cancer biology called cancer metabolism, which focuses on studying profound changes in metabolic activity in cancer cells. Through a mix of large-scale profiling of hundreds of cellular metabolites, x-ray crystallography, and innovative enzymology, the Agios team demonstrated that a single amino-acid substitution in the IDH1 active site allows the enzyme to acquire an entirely new activity to produce the metabolite 2HG. Analysis of tumor samples of brain cancer patients with the IDH1 mutation revealed up to hundred-fold elevations in concentrations of 2HG, a metabolite that has been previously linked to the formation of brain cancer.

“Agios’ founding principles included the belief that targeting important metabolic pathways of cancers could make a fundamental difference in the treatment of the disease. Our IDH1 discovery is a great example of the power of the team and of our approach in targeting cancer metabolic pathways. In just four months, scientists at Agios unraveled very complex biology to advance a new understanding of gliomas and the role of IDH1 and corresponding biomarkers,” said David Schenkein, M.D., Chief Executive Officer, Agios. “We are able to do this by utilizing a unique approach of integrating deep biology and leveraging our proprietary platform for cancer metabolism research.

“We are looking forward to developing potential therapeutics specifically targeting IDH1 for patients with these devastating diseases, and to leveraging our unique cross functional approach to cancer metabolism research in order to discover insights into other targets and pathways,” added Schenkein.