My research is centered on the posttranslational modifications of ubiquitin (UB) and small ubiquitin-like modifier (SUMO) and pathways targeted new anticancer drug discovery through collaboration with Dr. Hao. Initially, I worked on how the UB E3 ligase A20-mediated ubiquitination leads to the cancer resistance to TRAIL (tumor necrosis factor-related apoptosis ligand)-induced apoptosis (Cancer Discovery 2012; 2:140-55l ). Recently we discovered that SUMO1 modification pathway is elevated in cancers and drives the cell cycle and cancer progression (Nature Communications 2014;5:4234). Through cancer cell-based drug screening of NCI drug-like compounds library, we identified the small molecule SUMO1 inhibitor that we named and patented as the SUMO1-inhibition compound (SMIC1). CRISPR/CAS9 genome wide screening revealed the ubiquitination pathway that SMIC1 activates for SUMO1 protein degradation. Medicinal chemistry improved the potency and drug-like features of the hit compound SMIC1 and identified more potent SMIC1 analogs as the SMIC1 leads in drug development. Treatments of patient derived cancer xenografts (PDXs) with SMIC1 and its leads suppress the progression of patient derived cancer xenografts (PDXs).
Currently, my laboratory is working on the following three projects. The first project funded by the NIH/NCI SBIR grant aims to identify clinical development candidate from SMIC1 lead compounds through medicinal chemistry for investigative new drug (IND)-enabling studies and ultimately phase I clinical trial. The second project is to delineate the ubiquitination pathway for SUMO1 degradation in cancer and establish the novel biologic concept and pathway on how the protein modifier SUMO1 is modulated and controlled by another modifier UB. The third project is to develop TRAIL and SMIC1 combined treatment of cancers. TRAIL was approved as an anticancer drug, but failed in clinical trials in cancer therapy due to drug resistance. My lab has recently found that the death receptor-5 (DR5) of TRAIL is modified by SUMO1 and DR5-SUMO1 conjugation results in cancer resistance to TRAIL treatment. SMIC1 treatment abolishes DR5 SUMOylation and leads to TRAIL-induced apoptosis in cancer cells. This study will approve the new cancer therapy in combination of TRAIL and SMIC1.
Ph.D. - University of Caen, France 09/2002
M.Sc. - University of Caen, France 06/1999
