Steven Chan

At A Glance

• The goals of our research program are:
  1. to determine the role of mitochondria in the development and maintenance of leukemic stem cells in acute myeloid leukemia (AML), and
  2. to discover novel therapeutic strategies that target AML stem cells using functional genomic screens.
• To achieve these goals, our laboratory employs a range of genetic and analytical tools including CRISPR/Cas9 technology and genetically-encoded fluorescent biosensors in human-derived AML samples.
• We employ CRISPR/Cas9-based genetic screens to identify unique vulnerabilities associated with specific mutations in AML (synthetic lethal screens). In addition, these screens are used to identify therapeutic strategies against drug resistance mechanisms. 

Short Bio

Dr. Chan completed his undergraduate training (Immunology specialist program) at University of Toronto in 2000. He received his medical and research training at Stanford University in California where he earned his MD (2008) and PhD (2006) degree in Immunology. He subsequently completed his internal medicine residency (2010) and adult hematology fellowship (2014) at Stanford Hospital and Clinics. He conducted his postdoctoral research under the supervision of Dr. Ravindra Majeti at the Stanford Cancer Institute where he studied the isocitrate dehydrogenase mutation in acute myeloid leukemia and its effects on mitochondrial function. He joined Princess Margaret Cancer Centre as a Clinician Scientist in 2015.

Research Synopsis

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).

Recent Publications

• Mazumdar C, Shen Y, Xavy S, Zhao F, Reinisch A, Li R, Corces-Zimmerman MR, Flynn RA, Buenrostro JD, Chan SM, Thomas D, Koenig JL, Hong WJ, Chang HY, Majeti R. 2015. Leukemia-associated cohesin mutants dominantly enforce stem cell programs and impair human hematopoietic progenitor differentiation. Cell Stem Cell. 17(6):675-88.
• Chan SM*, Thomas D*, Reinisch A*, Majeti R. 2015. Biology and Clinical Relevance of Acute Myeloid Leukemia Stem Cells. Seminars in Hematology. 52(3):150-64. * First co-authors
• 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.
• Chan SM, Majeti R. 2013. Role of DNMT3A, TET2, and IDH1/2 Mutations in Pre-Leukemic Stem Cells in Acute Myeloid Leukemia. International Journal of Hematology. 98(6): 648-57.
• Chan SM, Weng AP, Tibshirani R, Aster JC, Utz PJ. 2007. Notch Signals Positively Regulate Activity of the mTOR Pathway in T Cell Acute Lymphoblastic Leukemia. Blood. 110(1): 278-86.
• Fathman CG, Soares L, Chan SM, Utz PJ. 2005. An array of possibilities for the study of autoimmunity. Nature. 435(7042):605-11.
• Chan SM, Ermann J, Su L, Fathman CG, Utz PJ. 2004. Protein microarrays for multiplex analysis of signal transduction pathways. Nat. Med. 10(12):1390-1396.
• Chan SM*, Garza KM*, Suri R, Nguyen LT, Odermatt B, Schoenberger SP, Ohashi PS. 2000. Role of antigen-presenting cells in mediating tolerance and autoimmunity. J. Exp. Med. 191(11): 2021-2027.  * First co-authors

Graduate Students

Alex Liu 
Yitong Yang