Image-guided Gene and Virotherapy for Pancreatic Cancer

DESCRIPTION (provided by applicant): Pancreatic adenocarcinoma is one (1) of the most lethal cancers in the United States, with an average survival of 3 to 6 months from the time of diagnosis. Currently available treatments have had little impact on the course of the disease. The goal of this research plan is to incorporate molecular imaging and image-guided interventional techniques to develop a new approach for the treatment of pancreatic cancer by using intratumoral injection of an attenuated measles virus (MV-Edm) genetically modified with the sodium-iodide symporter (NIS) gene (MV-NIS). MV-Edm was chosen for these studies because 1) MV-Edm infection causes massive cell-cell fusion, leading to a potent oncolytic effect in multiple human tumor models, and 2) NIS gene expression allows radioiodine-based in vivo imaging and therapy strategies. The propensity for local tumor invasion makes pancreatic cancer a compelling target for intratumoral gene delivery, owing to the potential value of local therapy. Our overall hypothesis is that image-guided intratumoral MV-NIS therapy combined with in vivo imaging of gene expression and therapeutic response will facilitate the development of genetically based therapies for pancreatic cancer. The specific aims are to 1) determine the sensitivity and resolution of radioiodine-based imaging techniques for in vivo monitoring of MV-NIS infection and gene expression in pancreatic cancer xenografts, 2) use these imaging techniques to determine the efficiency and enhance the uniformity of intratumoral MV-NIS delivery, and 3) determine the utility of NIS as a therapuetic transgene for 131 l radiovirotherapy. The proposed career development plan combines didactic course work in molecular medicine and gene therapy with a supervised laboratory-based research experience. The long-term goals are to 1) develop an independent laboratory-based and translational research career in image-guided cancer gene therapy, and 2) translate the results of our laboratory research into appropriate clinical trials and therapeutic strategies for patients who have locally advanced or metastatic pancreatic carcinoma.