At the time of diagnosis, a majority of pancreatic cancer patients already have local lymph node or distant metastases, which may or may not be detectable, but certainly contribute to the lethality of the disease and hence should be treated effectively. Chemotherapy is the standard line of treatment for advanced pancreatic cancer but the untargeted nature of the current chemotherapeutic regimens often results in poor efficacy and high toxicity. Radioimmunotherapy (RIT) is a 'smart'way of delivering radiation to the known and occult metastatic cancer cells and can be a promising therapeutic option for treating pancreatic cancer. Our previous studies have demonstrated that scFv fragments of anti-tumor antibodies due to their improved pharmacokinetics and biodistribution hold a greater potential than intact antibodies for solid tumor RIT. However, various physiological impediments encountered by macromolecule-based drugs in solid tumors have limited the efficacy of RIT in solid tumors. The two major barriers to macromolecule delivery in solid tumors are: a) insufficient and heterogeneous tumor blood flow, and b) obstructive nature of tumor stroma. Tumor vasculature is characterized by structural and functional anomalies as compared to normal vasculature and these differences result in differential responses when the normal and tumor vasculature are exposed to various vasoactive agents. Modulation of tumor stromal compartment can be achieved by selectively targeting the signalling pathways that regulate various components of tumor stroma. The central hypothesis of this proposal is: "Selective modulation of tumor vascular flow and tumor stroma would improve the delivery and therapeutic efficacy of targeted radiopharmaceuticals for the treatment of pancreatic cancer." A combination of, Angiotensin II (ATII), BQ123 [antagonist of endothelin-1 receptor type A (ETAR)] and cyclopamine [(inhibitor of sonic hedgehog signalling)] will be evaluated for improving the tumor uptake and improve tumor distribution and retention of radiolabeled scFvs without compromising their pharmacokinetic and tumor targeting properties. To test the hypothesis two specific aims are proposed: 1) Determine the relative biodistribution, tumor retention and pharmacokinetics of scFv constructs in the presence, absence and various combinations of penetratin, ATII, BQ123 and cyclopamine in transplantable pancreatic tumor xenografts in mice;and 2) Study the therapeutic efficacy of penetratin co-administered, 131I-labeled scFvs (administered as fractionated doses) in combination with ATII, BQ123 and cyclopamine in pancreatic tumor bearing mice. The preclinical results obtained from the proposed study will immediately form the basis of clinical trial in pancreatic cancer patients. The proposed studies represent the first comprehensive effort to overcome physiological barriers in solid tumor to improve efficacy. PUBLIC HEALTH RELEVANCE: The proposal aims to develop a novel combination therapy that combines the excellent tumor targeting and pharmacokinetics of genetically engineered anti- tumor antibodies with "tumor- selective" agents to modulate tumor blood flow and stromal compartment. A combined administration of Angnitensin II, endotehlin-1 receptor antagonist and sonic hedgehod signaling inhibitor with radioiodinated antibody fragments to result in improved biodistribution, unaltered pharmacokinetics and enhanced therapeutic efficacy of antibody-based radiopharmaceuticals for lethal pancreatic cancer.