The long-term goal of our laboratory is to understand how the antiapoptotic protein survivin and its splice variants (e.g., survivin-2B, survivin-ΔEx3, survivin-3B) play a role in tumorigenesis and cancer progression. Survivin plays critical roles in regulating the cell cycle and mitosis. The prominent expression of survivin appears in all human malignancies, and is low or absent in most normal tissue. This suggests that it would be an ideal target for cancer therapy.
Using cancer cell-based survivin-reporter systems via high throughput screening (HTS) of compound libraries, followed by in vitro and in vivo analyses of HTS-derived hit-lead compounds, we identified a small molecule FL118 and demonstrated that FL118 has significant antitumor activity in several human xenograft tumor animal models. We actively pursue opportunities to translate our laboratory findings to clinics.
Our current research focuses on: the molecular mechanisms of action of FL118, the DMPK profile and potential side effects induced by FL118 treatment. In addition, survivin isoforms perform different functions in distinct subcellular compartments. We characterized several novel survivin splicing variants and we are addressing their functions in cancer development and cancer treatment.
Our lab work is supported by NIH/NCI, DOD and many public or private foundations.
Ling X, Bernacki, RJ, Brattain, MG and Li, F, Induction of survivin expression by taxol (taxane paclitaxel) is an early event and is independent of taxol-mediated mitotic arrest. J Biol Chem., 279(15): 15196-15203, 2004 PMID: 14722122
Ling X, Cheng QY, Black JD and Li F, Forced expression of survivin-2B abrogates mitotic cells and induces mitochondria-dependent apoptosis by blockade of tubulin polymerization and modulation of Bcl-2, Bax and survivin. J Biol Chem., 282(37): 27204-14, 2007 PMID: 17656368
Ling X, Cao S, Cheng Q, Keefe JT, Rustum, YM and Li F, A novel small molecule FL118 that selectively inhibits survivin, Mcl-1, XIAP and cIAP2 in a p53-independent manner, shows superior antitumor activity, PLoS ONE, 7:e45571, 2012 PMID: 23029106
Ling X and Li F, An intravenous (i.v.) route-compatible formulation of FL118, a survivin, Mcl-1, XIAP, and cIAP2 selective inhibitor, improves FL118 antitumor efficacy and therapeutic index (TI). American Journal of Translational Research, 3(2): 139-154, 2013 PMID: 23573360
Ling X, Xu C, Fan C, Zhong K, Li F*, Wang X*: FL118 Induces p53-Dependent Senescence in Colorectal Cancer Cells by Promoting Degradation of MdmX, Cancer Research, 74:7487-7497, 2014