Day 2 :
University of Kansas Medical Center, Kansas City, Kansas
Keynote: Novel nutraceuticals GZ17-06.02 suppresses pancreatic cancer tumorigenesis and metastasis by inhibiting cancer stem cells
Time : 09:40-10:20
Dhar rcompleted his PhD from University of Calcutta in Physiology and did his post-doctoral training in University of Puerto Rico in Biochemistry and University of Missouri-Columbia in Pharmacology. Then, Dr. Dhar became Research Track Assistant Professor in Pharmacology, University of Columbia and then moved at University of Missouri-Kansas City School of Medicine as Associate Professor. He joined in the Department of Cancer Biology as an Associate Professor in University of Kansas Medical Center. Dr. Dhar has published more than 60 publications in the journals of international repute and about more than 10 reviews in thw area of his research
Purpose: Current therapeutic regimens have limited effectiveness in pancreatic adenocaricinom (PDAC). Novel therapeutic targets are needed to treat this disease. GZ17-06.02, novel nutraceutical, showed its anti-cancer properties in several cancers. We hypothesize that GZ17-06.02 will inhibit tumor progression and metastasis in PDAC.
Experimental Procedure: In this study, we have determined cell proliferation, pancosphere formation and apoptosis following treatment of different doses GZ17-06.02 in human pancreatic cancer cells. Cell cycle distribution and apoptosis were measured using flow cytometic analysis. Orthotopic pancreatic cancer model in athymic mice was developed and GZ17-06.02 was given orally for 20 days to those mice. Proliferative markers, pEGFR/pAkt and apoptotic markers, Bax/Bcl-2, were monitored following treatment with GZ17-06.02 in both in vivo and in vitro models. Metastatic markers, MMP-2 and MMP-9 were measured in metastatic tissues in orthotopic models.
Results: GZ17-06.02 inhibited proliferation of pancreatic cancer cell lines in a dose- and time-dependent manner. GZ17-06.02 induced apoptosis in both in vitro and in vivo pancreatic cancer. Moreover, the compound significantly inhibited epidermal growth factor receptor and Akt phosphorylation. Furthermore, GZ17-06.02 decreased the number and size of the pancospheres in S2-007 cells with concomitant inhibition of pancreatic cancer stem cell markers, DCLK1, Lgr5 and EpCam. The effect of GZ17-06.02 suppressed tumor growth and metastatic potential as indicative of MMP-2 and MMP-9 activity in primary and metastatic tumors.
Conclusions: GZ17-06.02 significantly inhibits pancreatic cancer stem cells, thereby suppressing tumorigenesis and metastasis in both in vitro and in vivo pancreatic cancer models.
Eastern Virginia Medical School, Norfolk, USA
Keynote: Conquering K-RAS-Driven Human Pancreatic Cancer by Attacking its Achilles' Heel, SIAH Proteolysis – A Major K-RAS Vulnerability and K-RAS Downstream Signaling “Gatekeeper”
Time : 10:20-11:00
Tang received a B.S. in Biophysics from Fudan University, and a Ph.D. in Biochemistry and Molecular Biology from Pennsylvania State University. She completed her postdoctoral training at UC Berkeley. Dr. Amy Tang is a Professor of Cancer Biology at Eastern Virginia Medical School. She is a lead pancreatic cancer researcher and a recipient of the national 2010 AACR-PanCAN Innovative Award. Dr. Tang and her research team have developed an innovative strategy to control and eradiacte oncogenic K-RAS-driven pancreatic cancer in preclinical and clinical settings. She has published more than 28 papers in peer-reviewed journals, and has served as an editorial board member at 6 scientfic journals.
Hyperactive K-RAS signaling is a major menace that drives aggressive cancer cell dissemination, tumor progression and systemic metastasis in human pancreatic cancer. Counteracting K-RAS hyperactivation in attempt to reverse malignant transformation and inhibit latent tumor spread is an important goal in pancreatic cancer biology. Instead of targeting an upstream signaling module such as EGFR/K-RAS/B-RAF/MEK/MAPK/ERK/AKT/mTOR, we targeted the most downstream signaling module in the K-RAS signaling pathway called the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of Seven-In-Absentia (SINA), an evolutionarily conserved RING E3 ligase, an essential downstream signaling module and a critical "gatekeeper" required for proper K-RAS signal transduction. We found that inhibiting SIAH function is highly effective to abolish well-established and late-stage pancreatic tumor growth and metastasis in our pre-clinical studies. These findings demonstrate that SIAH is indeed an attractive, logical and potent anti-K-RAS therapeutic target for us to develop new and effective anticancer strategy against human pancreatic cancer. Through our work, SIAH has emerged as a new and effective drug target against oncogenic K-RAS hyperactivation in pancreatic cancer. As one of the most evolutionarily conserved signalimng components, SIAH is ideally and logically positioned to become a next-generation anti-K-RAS drug target in human pancreatic cancer. By attacking this most downstream “gatekeeper” critical for the proper oncogenic K-RAS signaling transmission, we will be in a position to halt the genesis, progression and metastasis of the deadliest forms of human pancreatic cancer in the future. We aim to translate anti-SIAH therapy to benefit our pancreatic cancer patients in the clinic