Abstract IA007: Getting ahead of the tumor: Interception approaches for pancreas cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) emerges from precursor lesions (PanINs and IPMNs) that harbor mutations in the KRAS oncogene. Once thought to be untargetable, the KRAS oncoprotein can now be inhibited with small molecule compounds that bind to either the active or inactive form of the protein. KRAS inhibitors are in various stages of clinical development and stand to change the therapeutic landscape for advanced PDAC. Given the prevalence of KRAS mutations in PanIN precursors, we hypothesized that KRAS inhibition could decrease the amount of premalignant neoplasia in the pancreas, thereby “intercepting” the lesions before they can progress to advanced PDAC. To this end, we used the KPC mouse model of PDAC in which pancreas-directed mutations in KRAS and TP53 result in the formation of PanIN lesions and invasive carcinoma with reproducible kinetics. Short term KRAS inhibition led to PanIN regression via apoptosis and a modest delay in tumor onset, whereas prolonged inhibition – achieved via a metronomic on/off dosing schedule – led to a near-tripling over overall survival across multiple agents. These results underscore the feasibility of bringing KRAS inhibition forward from the malignant setting to intercept disease at the premalignant stage.