The primary objective of this research is the development of methods to improve radioimmunotherapy (RIT) of pancreatic cancer (PanC). PanC is the fourth leading cause of cancer death in men and women in the USA. RIT has potential of becoming a valuable tool in the treatment of PanC. Impressive responses to RIT have already been observed in lymphoma. By contrast, with rare exceptions, solid tumors have proven resistant thus far to RIT. Poor responses are rooted primadly in the physiology of solid tumors. Penetration of RIT is not homogeneous and only a minute fraction of injected doses reaches tumor. Poor blood supply, tight junctions between epithelial tumor cells and the large tumor stroma component typical of PanC create a formidable physical barrier to the RIT diffusion into the tumor mass. Two methods of improving RIT of PanC proposed in these studies deal with difficulties unique to pancreatic cancer: large tumor stroma and poor vascular permeability. The first approach is based on a previously unrecognized therapeutic potential of inhibition of the platelet derived growth factor receptor PDGFr-beta ST1571) in tumor stroma cells. The control of interstitial fluid pressure (IFP) is one of the known biological functions of PDGF-BB. PDGFr-beta are expressed in the stromal compartment of PanC, inhibitors of PDGFr-beta will improve RIT by reducing tumor IFP thereby increasing the uptake of radioimmunoconjugates, and consequently augmenting tumor responses to RIT. To achieve this objective a highly selective antagonist of PDGFr-beta STI571 (Gleevec) will be included in the RIT scheme to reduce tumor IFP and to increase the uptake of RIT in tumor. Preliminary studies indicate that tumor responses to RIT augmented with STI571 are improved by as much as 200%. There also appears to be a tumor-dependent response to the antagonist alone, i.e., a remarkable tumor growth delay is observed in response to STI571 in a mouse pancreatic adenocarcinoma model. Further improvements in the delivery of RIT are anticipated by the inclusion of agents that increase the vascular permeability (VP) of tumor blood vessels. The transport of RIT into tumors relies on VP of tumor vessels to macromolecules. Response- including levels of hypoxia, interstitial fluid pressure, changes in vasculature, proliferative and apoptotic fractions, and changes in tumor's radiosensitivity will be evaluated. This knowledge will ultimately lead selective conformationally biased agonist pepUdes (C5aAP) derived from the Cterminal domain of the human C5a complement substantially improve the outcome of RIT. Combination of both approaches are certain to bdng further improvements. Studies proposed here will define the role of these adjuvants in RIT of PanC and the mechanism of their action. Radiolabeled antibodies B72.3 and CC49 that recognize tumorassociated antigen TAG-72 will be evaluated in mouse models of PanC. Parameters such as the radioisotope uptake, tumor responses to augmented RIT, changes in tumor physiology, to improved clinical radioimmunotherapy of pancreatic cancer.
