Pancreatic cancer has a 90% mortality rate due to progression of disease at both the local/regional site and metastases to distant sites. The applicant proposes to develop a new treatment which combines the benefits of gene therapy and radioligand technology. The current limitations of radioimmunotherapy in man reflect low tumor antigen expression and restricted tumor penetration of antibody molecules. The applicant proposes to develop gene therapy vectors to induce tumor cells to express high levels of membrane receptors with high affinity for peptide ligands which can be constructed to carry radioisotopes. These ligands are low molecular weight to enhance tumor penetration and will utilize isotopes which deliver radiation to several tumor cell diameters (distance) to compensate for less than universal tumor cell transfection rates. The applicant will address the local tumor site using murine models of human pancreatic cancer using intratumor and systemic vector strategies. Studies of localization of radiolabeled peptides in metastatic sites will utilize a murine hepatic metastases model and systemic administration of tropism-modified adenoviruses or adenoviruses under the control of tumor-specific promoters. The design and testing of appropriate radiolabeled ligands will be developed concurrently to optimize dose, schedule, biodistribution, therapy, and toxicity issues. These studies will develop this unique paradigm of gene therapy/radiation therapy which will provide information valuable to therapy of other cancers as well.
