Bingliang Fang, MD
Associate Professor, University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

Abstract:

Cancer is a multipathway disease caused by multiple genetic and epigenetic changes in somatic cells that affect a number of signaling pathways. Mutation analyses on primary cancers for genes encoding kinases or genes with known relationships to cancers have revealed that several important signaling pathways might cooperatively be involved in oncogenesis. Evidences have demonstrated that interrupting a single pathway was often insufficient to induce cancer cell death because redundant inputs from different pathways drive and maintain downstream signaling. Consequently, combination of targeted agents but not single agents, is frequently required for effective anticancer therapy, and numerous combination regimens of targeted agents are currently under investigation at either preclinical or clinical levels. We hypothesize that agents which can modulate functions of multiple targets and/or multi-pathways, and induce apoptosis in a subset of tumor cells will provide new opportunities for anticancer therapy. We have developed such multi-pathway modulating agents through synthetic lethality screening on isogenic human ovarian epithelial cells with and without K-Ras mutations. Those agents suppress phosphorylation of C-terminal domain of RNA polymerase II, disrupted the interaction between protein kinase Ci (PKCi) and the cyclin T1/cyclin-dependent protein kinase 9 (cyclin T1/CDK9) complex, suppressed JAK/Stat3 signaling pathway, and induced sustained JNK activation through inhibition of JNK dephosphorylation. Some of them are currently under preclinical evaluation through NCI’s Rapid Access to Intervention Development (RAID) Program and have shown to induce complete tumor regression or suppressed tumor growth in vivo in xenograft tumor models, demonstrating the potential feasibility of using those agents for cancer therapy.

Keywords: Molecules, Apoptosis, MAP kinase, RNA polymerase, Cancer Therapy.