Jonathan Trent, MD, PhD, University of Miami, Miami, FL, details the identification of mutant isocitrate dehydrogenase 1 (IDH1) enzymes as key factors in the migratory tumor phenotype in most cases of conventional chondrosarcoma. Mutations the IDH1 gene give rise to this mutant, resulting in a buildup of the oncometabolite D-2-hydroxyglutarate (2-HG), which interferes with antitumor enzymes and furthers the expression of integrin proteins critical for metastasis. CRISPR technology was key in uncovering this, and using this research as a basis, a clinical grade mutant IDH1 inhibitor, ivosidenib (AG-120), has been developed. A Phase I study in patients with advanced chondrosarcoma noted that the drug was well tolerated, and most cases of conventional chondrosarcoma only benefited, with over 50% of these patients achieving PFS for 6 months. The same benefits were not noted in cases in which other gene mutations where also present, as these mutations contributed to the migratory phenotype instead. Further trialing of ivosidenib alongside other therapies is needed to develop an effective treatment for such patients. This interview took place at the ESMO Sarcoma and Rare Cancers Congress 2023 in Lugano, Switzerland.
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