Our translational research group is dedicated to the development of innovative pancreatic cancer (PC) therapeutics. We have identified and characterized a novel PC related oncogene (the Cancer-associated Sm-like oncogene(CaSm)) and shown that: 1) it contributes to the transformed state in human and murine PC cells, and 2) adenovirus expressing CaSm antisense RNA (Ad-DhCaSm) significantly reduces in vitro and in vivo tumor growth with prolonged survivorship via cyclin B1/CDK1 dependent cytostatic cell cycle inhibition. These results indicate that the CaSm oncogene is critical to PC cell cycle control and could be targeted for therapeutic intervention. One of the major barriers to an effective CaSm-based gene therapy approach is achieving adequate in vivo tumor delivery. In fact, insufficient and/or non-effective delivery of gene vectors is a global problem limiting cancer gene therapy. We have recently established an exciting collaboration with Dr. Jesse Au's laboratory (Ohio State) that has developed a novel paclitaxel tumor priming approach capable of enhancing the delivery large molecules throughout an intraperitoneal tumor. Furthermore, we now have preliminary studies suggesting that the down-regulation of CaSm may induce a bystander effect in vivo- which could alleviate the need for delivery of the CaSm anti-sense gene to 100% of PC cells in vivo. Utilizing the downregulation of CaSm as a novel therapeutic intervention and our recently characterized murine CaSm PC model, our specific aims are to: 1) Determine whether paclitaxel tumor priming improves delivery and efficacy for pancreatic cancer gene therapy, 2) Define the impact of tumor priming on, and the mechanisms by which, the reduction of CaSm over-expression mediates a bystander effect, and 3) Define the mechanism by which CaSm upregulation leads to PC oncogenesis. The focus of this proposal is to combine a novel tumor priming approach with a promising gene target in order to develop innovative PC therapeutics. Successful completion of the proposed studies will advance the research in treatment of pancreatic cancer and, on a broader scope, validate an innovative technology for delivering gene vectors or other nanoparticles to intraperitoneal tumors

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Developmental Therapeutics Study Section (DT)
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Arya, Suresh
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Medical University of South Carolina
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United States
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Wang, Jie; Lu, Ze; Wang, Junfeng et al. (2015) Paclitaxel tumor priming promotes delivery and transfection of intravenous lipid-siRNA in pancreatic tumors. J Control Release 216:103-10
Lu, Ze; Tsai, Max; Wang, Jie et al. (2014) Activity of drug-loaded tumor-penetrating microparticles in peritoneal pancreatic tumors. Curr Cancer Drug Targets 14:70-8
Wang, Jie; Lu, Ze; Yeung, Bertrand Z et al. (2014) Tumor priming enhances siRNA delivery and transfection in intraperitoneal tumors. J Control Release 178:79-85
Camp, E R; Wang, C; Little, E C et al. (2013) Transferrin receptor targeting nanomedicine delivering wild-type p53 gene sensitizes pancreatic cancer to gemcitabine therapy. Cancer Gene Ther 20:222-8
Little, Elizabeth C; Wang, Cindy; Watson, Patricia M et al. (2012) Novel immunocompetent murine models representing advanced local and metastatic pancreatic cancer. J Surg Res 176:359-66
Wang, Jie; Lu, Ze; Gao, Yue et al. (2011) Improving delivery and efficacy of nanomedicines in solid tumors: role of tumor priming. Nanomedicine (Lond) 6:1605-20
Lu, Ze; Wang, Jie; Wientjes, M Guillaume et al. (2010) Intraperitoneal therapy for peritoneal cancer. Future Oncol 6:1625-41