International Conference on Pancreatic Disorders and Treatment October 17-19, 2016 Chicago, Illinois, USA

Biography:

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

Abstract:

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.

Biography:

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.
 

Abstract:

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

Biography:

Dr. Arlen serves as the Director of Scientific Affairs for Precision Biologics.  He is involved in a consulting capacity, providing his renowned expertise as both senior scientific and clinical advisor for product development. He was trained as a cancer surgeon at Memorial Sloan-Kettering where he remained on staff for 20 years involved in the surgery of advanced cancer problems and the immunotherapeutic approaches to managing the patients. Dr. Arlen established the Surgical Oncology Division at North Shore University Hospital, and formed a practice group (North Shore Surgical Oncology Associates). He has written two major textbooks and published over 100 journal articles related to cancer treatment and tumor Immunology.

Abstract:

Pancreatic carcinoma in of itself is a relatively lethal malignant disease process.  Even when the tumor  is small and virtually confined the the pancreatic head where the prognosis is best when compared with  body and tail lesions, the overall survival ranges from  5-10 % even following whipple resection.  Usually within the short interval of evaluaton of the lesion, nodal and or  distant mets is noted with limited survival. Multiple chemotherapeutic forms of intervention have been attempted employing combination drug therapy ie FOLFIERI as well Gemcitabine  alone and in combination with Abraxane.  These appear  offer on average a 3-5 month survival advantage over no intervention. With the discovery of those immunogenic proteins that characterize pancreatic cancer,  the opportunity for enhancement in survival using specific active immunotherapy has become a possibility  Three oncofetal proteins have now been characterized and represent post translational modifications of mutated MUC5ac, mutated CEAcam5/6  and a mutated form of A33 not previously described.  In order to sequence these immunogens for immuno- therapy, monoclonal antibodies were developed for immunopurification , structural identification and sequencing of the antigen.  On examination of the antibodies to the target immunogens,  it became evident that when immunization was initiated with partially purified protein, the improved survival was a consequence of an ADCC phenomenon and not related to cytotoxic T cell responses to the tumor. The naked MUC5ac antibody, Neo-102 has been used in FDA approved Phase 1/2 studies and is being prepared for Phase III investigation with the monoclonals alone and in combination with chemotherapy.  With the ability to radiolabel the antibodies for RT and with the possible addition of checkpoint inhibitors and those lymphokines enhancing the antitumor effects of the mAb the potential of total control of the disease becomes a possibility.

Biography:

Christine Mehner has completed her MD at the University of Witten/Herdecke, Germany and became a postdoctoral fellow at the Mayo Clinic Cancer Center, Jacksonville, FL. She has published multiple first author papers in the field of cancer research, in reputed journals that have been recognized by the Faculty of 1000 and have been featured in news and media. She has been serving as an editorial board member and constant reviewer for various journals.

Abstract:

Pancreatic ductal adenocarcinoma (PDA) arises at the convergence of genetic alterations in KRAS with a fostering microenvironment shaped by immune cell influx and fibrotic changes; identification of the earliest tumorigenic molecular mediators evokes the proverbial chicken and egg problem. Matrix metalloproteinases (MMP) are key drivers of tumor progression that  originate primarily from stromal cells activated by the developing tumor. Here, MMP3, known to be expressed in PDA, was found to be associated with expression of Rac1b, a tumorigenic splice isoform of Rac1, in all stages of pancreatic cancer. Using a large cohort of human PDA tissue biopsies specimens, both MMP3 and Rac1b are expressed in PDA cells, that the expression levels of the two markers are highly correlated, and that the subcellular distribution of Rac1b in PDA is significantly associated with patient outcome. Using transgenic mouse models, coexpression of MMP3 with activated KRAS in pancreatic acinar cells stimulates metaplasia and immune cell infiltration, priming the stromal microenvironment for early tumor development. Finally, exposure of cultured pancreatic cancer cells to recombinant MMP3 stimulates expression of Rac1b, increases cellular invasiveness, and activation of tumorigenic transcriptional profiles.

IMPLICATIONS: MMP3 acts as a coconspirator of oncogenic KRAS in pancreatic cancer tumorigenesis and progression, both through Rac1b-mediated phenotypic control of pancreatic cancer cells themselves, and by giving rise to the tumorigenic microenvironment; these findings also point to inhibition of this pathway as a potential therapeutic strategy for pancreatic cancer.