Building on unique biological insights into cancer, Agios is creating a broad portfolio of first-in-class anticancer drugs targeting cancer metabolism that disrupt the metabolism, growth and survival of cancer cells. Agios’ research capabilities are also well-suited to developing companion diagnostics for each of our products to ensure the right patients are treated with our medicines.
Agios is conducting breakthrough research into multiple cancer metabolism targets. Currently disclosed discovery programs include key cellular targets: IDH1, IDH2 and PKM2.
Groundbreaking research by Agios' scientists (published in the November 22, 2009 journal of Nature) established for the first time that the mutated metabolic gene IDH1 has novel enzyme activity consistent with a cancer-causing gene or oncogene.
This 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 cancer), as well as other forms of cancer. This discovery appears to reverse the previously held belief that IDH1 did not have an impact on cancer-causing activity. This research also represents one of the first reported cases wherein a metabolic enzyme is shown to play a role in cancer formation, in this case through altered metabolic activity.
More recently, mutations in both IDH1 and a related enzyme IDH2 have been observed in patients with acute myelogenous leukemia (AML). Agios scientists have shown that these mutations also produce high levels of 2HG (published in the Journal of Experimental Medicine).
These findings create an opportunity to develop new treatments, targeting the IDH1 and IDH2 metabolic pathways, for brain cancer, AML and other cancers in which IDH1 or IDH2 mutations are present. Agios’ identification of 2HG, an exciting new biomarker, could potentially be used to develop an important new cancer diagnostic.
- "Cancer-associated IDH1 mutations produce 2-hydroxyglutarate." Dang et al., Nature, 2009
- "Cancer-associated metabolite 2-hydroxyglutarate accumulates in acute myelogenous leukemia with isocitrate dehydrogenase 1 and 2 mutations." Gross et al., Journal of Experimental Medicine, 2010
- "The Common Feature of Leukemia-Associated IDH1 and IDH2 Mutations Is a Neomorphic Enzyme Activity Converting a-Ketoglutarate to 2-Hydroxyglutarate." Ward et al., Cancer Cell, 2010
Agios' founders published important research (in the March 13, 2008 journal of Nature) showing for the first time that altered metabolic processes drive tumor growth. Previously, scientists believed that metabolic changes were a consequence of the cancer.
This study demonstrated how cancer cells “switch on” the same metabolic enzymes as those found in fetal cells to promote rapid growth, explaining why cancer cells are able to divide and grow more efficiently than normal cells. This research also identified the regulation of the M2 form of pyruvate kinase (PKM2), an enzyme involved in glucose metabolism, as an important mechanism behind this process, providing a target for the development of future cancer therapies.
In November 2011, Agios expanded its focus to developing drugs against targets in inborn errors of metabolism. This effort builds on the same capabilities for studying diseases of cellular metabolism that Agios has pioneered in the field of cancer metabolism. Inborn errors of metabolism are a class of genetic diseases caused by mutations/defects of single metabolic genes. These mutations cause the accumulation of substances that interfere with normal metabolic function of the body’s cells. Current treatment options for these disorders are limited, and Agios believes that targeting the specific metabolic pathways impacted in these disorders will provide a new avenue for developing important new therapeutic options for these patients.