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drug discovery programs

translating cutting-edge research into transformational therapies

Agios is actively working on numerous research and discovery projects in the field of cancer metabolism, including target identification, target validation, and therapeutic discovery and development.

The unique leadership position that Agios has established in the field of cancer metabolism can be seen in the breakthrough research in with two key cellular targets: PKM2 and IDH1.

PKM2

Key research by Agios founders – published in the March 13, 2008 journal of Nature – showed for the first time that altered metabolic processes drive tumor growth, versus being a consequence of the cancer.

• "Pyruvate kinase M2 is a phosphotyrosine binding protein." Christofk et al., Nature, 2008
  
  
• The M2 splice isoform of pyruvate kinase is important for cancer metabolism and tumor growth.” Christofk et al., Nature, 2008

This study showed 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 better than normal cells. The research also identified the regulation of 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 the study, the researchers found cancer cells utilize metabolic function more like fetal cells, promoting extremely rapid growth differently from that of normal adult tissue. Specifically, the study's findings include:

• In contrast to the forms of pyruvate kinase found in most normal adult tissues, only PKM2, which is found in fetal cells, was the only isoform of pyruvate kinase found in cancerous tissue.
• The researchers confirmed that only cells which express PKM2 enables the unique glucose metabolism seen in cancer cells, thereby allowing these cells to make tumors in vivo.
• The researchers confirmed that by re-expressing PKM2, cancer cells acquire the ability grow in vivo.

The study's exciting conclusion: as PKM2 is believed to be in all types of cancer cells, is not found most normal adult tissues, and it is critical for tumor formation, and as such, it potentially represents a powerful target for cancer therapy.

IDH1

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 a novel enzyme activity consistent with a cancer-causing gene, or oncogene.

• "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 ?-Ketoglutarate to 2-Hydroxyglutarate." Ward et al. Cancer Cell 2010
  
  

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 cancers, as well as other forms of cancer. 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.

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