Dr. Steven Chan’s research focus has been to develop novel approaches to target mutations that have been identified through whole genome sequencing efforts in the past 10 years. Although our understanding of the underlying mutations that drive cancer has tremendously improved, the majority of the mutations are unfortunately not easily “druggable” in part because many of them result in a loss-of-function phenotype. If the goal of personalized medicine is to be realized, new therapeutic strategies that specifically target these mutations are required in the armament of drugs. Dr. Chan views this as one of the main challenges facing translational cancer research today.
Chan SM, Thomas D, Cores-Zimmerman MR, Xavy S, Rastogi S, Hong WJ, Zhao F, Medeiros BC, Tyvoll DA, Majeti R. 2015. Isocitrate Dehydrogenase 1 and 2 Mutations Induce BCL-2 Dependence in Acute Myeloid Leukemia. Nature Medicine. 21(2):178-84.
In the above manuscript, Dr. Chan applied the synthetic lethality strategy to target the isocitrate dehydrogenase (IDH) mutation in AML. IDH mutations are clinically relevant because approximately 15% of AML patients have mutations in either IDH1 or IDH2. Using a functional genomics approach, he identified and validated the BCL-2 gene as a synthetic lethal target against IDH mutations. He further showed that pharmacologic inhibition of BCL-2 with ABT-199 (also known as venetoclax), an orally bioavailable and highly specific BCL-2 inhibitor, preferentially killed AML cells harboring IDH mutations. Furthermore, using xenotransplant models of human AML disease, Dr. Chan demonstrated that ABT-199 has activity against the leukemic stem cells which are responsible for disease relapse in patients. Finally, he showed that the sensitization effect is likely due to inhibition of a specific enzyme complex in the mitochondrial electron transport chain by 2-hydroxyglutarate, the oncometabolite that is generated by the mutant IDH enzymes.
Results of this work were published in the high-profile journal Nature Medicine (IF = 27.3) in January of 2015. His work was highlighted in several commentaries published in Cancer Cell (Pronier and Levine 2015), Nature Medicine (Verma and Steidl 2015), Cancer Discovery, and the American Society of Hematologist’s monthly periodical, the Hematologist (June 2015 issue).