TARGETING THE CASM ONCOGENE AS A NOVEL THERAPY FOR PANCREATIC CANCER

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DESCRIPTION (provided by applicant): 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