Research Summary

I discovered novel targets using high-throughput gene-expression based technologies using “on/off” signatures for differentiation and validating them in acute myeloid leukemia (AML) (J Clinical Investigation 2012). We identified glycogen synthase kinase-3 alpha (GSK-3α) as a novel target in AML, leading to the development of GSK-3 isoform selective inhibitors, a patent, and licensing agreement. We validated SYK inhibitors and their regulation of mTOR signaling in AML (Leukemia 2013). Finally, we investigated the role of MTHFD2 in AML (J Experiment Med 2016), which I have applied to my work in Chronic Lymphocytic Leukemia (CLL).

I am currently following cohorts of patients to evaluate the impact of implementing novel medications, and reporting unknown toxicities along with the impact of bioenergetics ex vivo (Blood 2017, Current Oncology 2019, Cancers 2020, 2021). This work spearheaded collaborations with Drs. D. Dawe, K. Decker, A.Marshall and M.Jones resulting in a translational grant being awarded by CIHR (2019). This Geroscience team grant led by Dr Dawe, aims to understand aging and frailty in CLL and in parallel the impact on mitochondria. It has also enabled me to pursue my interest in sex differences in blood cancers with funding from the HCL Foundation. It also enabled a grant from Lymphoma Canada to evaluate the impact of noveI agents in clinical practice and their costs. I also am an expert in NAMPT in cancer (CCR 2014, Oncotarget 2017). My lab investigates the role of metabolism in blood cancers. We established that NAMPT can be targeted by FK866 leading to cancer cell specific death by apoptosis (Clinical Cancer Research 2014) using flow cytometry and western blot analysis in primary CLL patient samples. This led to a collaboration with Dr. H. Kovar in Vienna, Austria, where my lab tested the impact of NAMPT inhibition on knockdown of EWS-FLI in Ewing’s Sarcoma cell lines using lentiviral techniques and evaluated their mitochondrial bioenergetics (Oncotarget 2017). My lab infrastructure includes an Acea NovoCyte 96-well flow cytometry platform, to perform the assays on the drug combinations described in the proposal, and an Oroboros oxygraph to characterize mitochondrial bioenergetics (using respirometry) in suspension cells. The results obtained from these findings was recently published in Cancers 2020 and 2021. The availability of the Proteomics platform and Collaborations with Dr. R. Zahedi and the establishment of multi-omic platforms at CCMR will enable us to continue to evaluate the impact of novel therapeutics on the mitochondria and leverage that knowledge for novel discoveries as recently demonstrated with Dr. S. Katyal and with Dr. T. Sharif. It will also enable the development of collaborations locally and beyond.