Pancreatic ductal adenocarcinoma (PDA) is one of the most lethal forms of cancer because of its aggressive growth and because diagnosis typically is made at a stage by which metastasis has already occurred. We are limited in our ability to treat PDA by an incomplete understanding of the biological mechanisms that govern cell proliferation, or the derangements in these mechanisms that permit pathological proliferation within the primary organ and at metastatic sites. In our recent studies in the mouse we have discovered a signal feedback circuit between epithelium and stroma that appears to be a central control mechanism governing proliferative activity in endodermal organs. This proliferative control circuit involves reciprocal signaling between epithelium and stroma, with the Hedgehog (Hh) signal produced in the epithelium and Wnt and other signals in the stroma. We propose to test the role of this epithelial/stromal circuit genetically and pharmacologically in PDA and, in particular, the effects of drug treatments designed to simultaneously disrupt this proliferation control circuit in both the epithelial and stromal compartments. This approach may serve as a new model for therapy of PDA. The Hh signaling pathway is known to play a key role in the pathophysiology of PDA, as cells of the tumor express the Sonic hedgehog (Shh) signaling protein; this signal activates Hh pathway response in pancreatic stroma, contributing to the desmoplastic reaction typical of PDA by inducing proliferation of stromal cells. Response to Hh in the stroma also increases the production of several other signals, including Wnts, which appear to act in a reciprocal paracrine loop by activating Wnt response and stimulating proliferation of tumor cells. The desmoplastic reaction and other features of human PDA are faithfully recapitulated in the mouse model of endogenous PDA selected for our work, in which tumorigenesis is driven by epithelial expression of oncogenic K-ras. We will test Hh pathway antagonists in combination with agents that target the epithelial component, including Wnt or oncogenic K-ras signal transduction inhibitors. This analysis will be streamlined by the use of newly developed ultrasound techniques capable of detecting and measuring pancreatic tumors in vivo at millimeter resolution, thereby reducing the requirement for lengthy studies that measure survival in the testing of drug treatments. We aim to rapidly improve therapy for PDA by: (i) establishing the validity of a strategy that employs combinations of targeted agents to simultaneously attack epithelial and stromal components of PDA; and (ii) providing a concrete basis for design and implementation of early clinical trials with drugs that are FDA- approved or in advanced stages of clinical testing. In addition, this work may serve as a paradigm for treatment of malignant disease arising in other endodermal organs.