I joined the Letai lab after completing my PhD in Cancer Biology at MD Anderson Cancer Center. My dissertation research focuses on targeting mitochondrial apoptotic pathways and overcoming cancer cell resistance. We demonstrate that targeting mitochondrial apoptosis is an effective approach to kill resistant tumor bulk cells and stem cells (Pan, et al., Cancer Discovery 2014; Pan, et al, Blood 2015). Our work demonstrates that AML cells are dependent on Bcl-2 for survival, which forms the basis for a multi-center trial of ABT-199/venetoclax in relapsed and refractory AML.
In a following project (Pan, et al., Cancer Cell 2017), We demonstrate that resistance to Bcl-2 inhibition can result from acute induction of Mcl-1 or chronic upregulation of Mcl-1, but p53 activation can effectively overcome Mcl-1-mediated resistance. Mechanistically, p53 activation regulates MAPK/GSK3 signaling to regulate Mcl-1 phosphorylation and promote its proteasomal degradation. Surprisingly, we find that p21 (highly induced upon p53 activation) triggers reversible G1-arrest to protect cancer cells from apoptosis. Nevertheless, Bcl-2 inhibition can overcome this resistance by switching the cellular outcomes of p53 activation from pro-survival G1-arrest to apoptosis. Taken together, Bcl-2 inhibition and p53 activation reciprocally overcome leukemia resistance to either strategy alone. The combinatorial strategy also has unprecedented efficacy in several mouse models of drug resistance and has been translated into a phase II trial at 19 cancer centers in US, Canada, France, and Italy. I have also gained expertise in various molecular techniques and developed a marker-recyclable method for repetitive genome editing in yeast (Pan, et al., FEMS Yeast Research, 2011).
Immune system is a powerful arsenal to fight against cancers. There are several intriguing overlaps between cancer immunotherapy and targeting mitochondrial apoptosis. Here lies my interest and I believe that combining these two emerging therapeutic approaches, that potentially complement each other, holds great promise for cancer treatment.
In my spare time, I enjoy running, cooking, good music, movies, and most importantly, playing Ping Pong!
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