The University of Texas MD Anderson Cancer Center
Department of Experimental Therapeutics
My research has focused on ovarian cancer tumorigenesis and function of tumor suppressors. Our group has identified ARHI (DIRAS3), an imprinted tumor suppressor gene that is downregulated in 60% of ovarian cancers. We first demonstrated that the re-expression of ARHI at physiologic levels in ovarian cancer cells inhibits cancer cell growth by initiating autophagy and inducing necroptotic cell death. DIRAS3 induces autophagy through several mechanisms including downregulation of mTOR, inhibition of FOXO3a phosphorylation, displacing Bcl-2 from Beclin1, breaking Beclin1 dimers and participating directly in the autophagy initiation complex (AIC) with Beclin1. DIRAS3 is also required for the induction of autophagy induced by amino acid starvation and mTOR inhibitor treatment. We have been studied the impact of amino acid deprivation in ovarian and breast cancers which let us to better understand the short-term and long-term epigenetic processes, and regulation of the transcription factors resulting in upregulation of DIRAS3, which leads to the development of autophagy and tumor dormancy.
Recently, I have also focused my efforts on studying the regulation of paclitaxel sensitivity and exploring therapeutic approaches to overcome chemo-resistance in ovarian cancer. We have found that inhibition of salt inducible kinase 2 (SIK2) can enhance paclitaxel sensitivity by inhibiting AKT signaling and blocking centrosome splitting during mitosis. A highly selective small molecule inhibitor of SIK2 kinase will be evaluated in Phase I/II clinical trials beginning early 2018. Additionally, we have identified a new role of phosphofructo-2-kinase/fructose-2,6-bisphosphate (PFKFB2) in ovarian and breast cancers. We have shown for the first time that PFKFB2, a glycolytic enzyme, drives tumor cell growth and regulates paclitaxel sensitivity by inducing apoptosis and G1 cell cycle arrest. These findings highlight a remarkable degree of coordination between cancer metabolism with cell proliferation and chemo-sensitivity, which may provide a novel target in patients with ovarian cancers and breast cancers where TP53 function remains intact.
Education & Training
M.D. - Suzhou Medical College - 1985