Ziqi “Christine” Yu
Hyperactivation of Mutant IDH1 as a Strategy Against Cancer
Abstract
Somatic mutations in isocitrate dehydrogenase (IDH) are found in deadly cancers such as acute myeloid leukemia and glioma. Mutant IDH (mIDH) enzymes abnormally produce 2-hydroxyglutarate (2HG), which promotes oncogenesis by reprogramming chromatin and blocking cell differentiation. Inhibition of mutant IDH enzymes effectively reduces 2HG and benefits some patients with IDH-mutant cancers, but most IDH-mutant tumors are impervious to 2HG inhibition. Even in responsive cases, resistance invariably develops. Our lab found that genetic or pharmacologic hyperactivation (rather than inhibition) of mitochondrial mIDH2 unleashes metabolic toxicity that selectively kills IDH2-mutant cancer cells. However, it is unclear whether enzyme hyperactivation can be used to target cancers with cytosolic IDH1 mutations. Here, we hypothesize that hyperactivation of mutant IDH function will raise 2HG to toxic levels and selectively kill mIDH1-driven cancers, paving the way for more effective therapies.
The PhRMA Foundation fellowship will support my work uncovering metabolic vulnerabilities in IDH-mutant cancers and exploring new therapeutic strategies with the potential to make a real clinical impact. As an international researcher, I am especially grateful for this recognition and for one of the rare funding opportunities that supports my continued career development in science.
