Our research activities center on the molecular genetics and biology of cancer with a focus on the identification, characterization, and therapeutic targeting of novel genetic events involved in the genesis and progression of brain cancers. Through comprehensive elucidation of genetic alterations in brain tumors, we have revealed novel genes for diagnostic, prognostic, or therapeutic purposes, as well as subclassification of patients that may preferentially respond to particular targeted therapies.
Gliomas are the most common type of primary brain tumor. Through exome sequencing, we have identified mutations in the NADP+-dependent isocitrate dehydrogenases (IDH1 and IDH2) in 70% of progressive malignant gliomas. These are somatic missense mutations that alter a conserved arginine residue and gain a neomorphic activity. A new metabolite produced by the glioma cells impacts on chromatin modulation and genome methylation. Patients with IDH1 and IDH2 mutations represent a discrete group of glioma patients. Our long-term goal is to develop a novel molecular-based glioma classification system and a targeted therapy on the basis of IDH1 and IDH2 mutations, their partner genetic changes, such as TP53, ATRX, CIC and FUBP1, and the involved oncogenic and metabolic pathways. Studies involving cell line and animal models, enzymatic study, metabolome and epigenome, are being investigated to determine the consequences of IDH mutations on cancer cell development. Study of alterations in these metabolic enzymes may provide insights into the metabolism and epigenetic regulation of cancer cells and provide novel avenues for development of anticancer therapeutics.