Pancreatic ductal adenocarcinoma (PDAC) has the worst survival of any major tumor type. At diagnosis, most tumors have invaded or metastasized, limiting treatment to systemic therapies with a modest impact on survival. Consequently, there is a pressing need to eradicate tumors before they reach more advanced stages. While early detection for PDAC remains elusive, cancer interception – a strategy that eliminates premalignant lesions before progression to invasive cancer – is an attractive complementary approach. Distinct from either prevention or treatment, cancer interception involves intervening when neoplasms are at an incipient stage. Colonoscopy – an example of “mechanical interception” – represents a successful application of this strategy, in which periodic removal of premalignant colon adenomas has markedly reduced colorectal cancer incidence and mortality. Similar approaches remove early lesions in the cervix, breast, and skin, but such procedures are only practical in easy-to-access tissues with readily identifiable and anatomically defined precursors, making them unsuitable for other solid tumors such as lung, liver, or pancreas cancer. The goal of this proposal is to advance translatable strategies with the potential to interrupt PDAC natural history in high-risk patients. Most PDACs arise from well-recognized precursors known as pancreatic intraepithelial neoplasias (PanINs) and intraductal papillary mucinous neoplasms (IPMNs). As these lesions progress to frank malignancy, they fashion a protective tumor microenvironment (TME) consisting of a dense “desmoplastic” stroma, paucity of blood vessels, and immunosuppressive myeloid cells. These changes are recapitulated in the KPC model of PDAC, which incorporates oncogenic mutations in KRAS and TP53. KPC mice develop PanIN lesions with predictable kinetics (6-9 weeks of age), making this model an ideal platform for exploring PDAC interception strategies. Our preliminary studies with KRAS inhibitors provide strong support for the feasibility of interception approaches. Here, we hypothesize that critical interactions between epithelial and stromal cells constitute a “pre-TME network” that is essential for PanIN lesions to progress to cancer. We further hypothesize that pharmacological disruption of the network will cause its collapse, resulting in effective PDAC interception. Because interception can only be studied in the setting of pre-malignant progression, our existing KPC infrastructure (“Penn Mouse Hospital”), together with experienced bench and clinical research teams, uniquely position us to test these hypotheses in animal models and human patients through three Specific Aims: Aim 1. Determine interception strategies for PanIN lesions and the impact of interception on the pre-TME Aim 2. Enhance the durability of interception Aim 3. Conduct a pre-surgical clinical trial to evaluate PDAC interception in high-risk patients