Targeting CDK4/6 as an interception strategy for intraductal papillary mucinous neoplasia

ABSTRACT Intraductal papillary mucinous neoplasms (IPMN) are common cystic neoplasms of the pancreas that may progress to pancreatic ductal adenocarcinoma (PDAC), a lethal disease with a current 5-year survival rate of 12%. The management for patients with IPMN high-risk features, mandates surgical resection in patients fit for surgery. While surgical resection is curative for some individuals, pancreatectomy carries significant risk of postoperative morbidity, and IPMNs reoccur in 30 – 60% of patients with invasive disease. Strikingly, 4-5% of patients with IPMN biopsies containing pathological features that reveal high grade dysplasia will be diagnosed with invasive PDAC within 5 years of their pancreatectomy. As such, identifying effective interception strategies for IPMN is a significant unmet need. Here we have based our research approach on reverse translational experiments where we have identified that the presence of co-oncogenic driver mutations in KRAS and GNAS renders multiple cancer types originating from different organs susceptible to CDK4/6 inhibition in patients. As ~70% of IPMN tumors contain KRAS and GNAS co-mutation, here we will determine the impact of CDK4/6 inhibition on IPMN tumor progression in genetically modified mice and PDX models of IPMN, where we can tightly regulate the timing, dosing, tumor genetics, as well as analyze tumor responses in pre-clinical models. In addition to studying endpoints of tumor progression and survival, we will determine the effects of CDK4/6 inhibition on the tumor microenvironment of IPMN. The results of these studies will provide key translational data that will propel future human clinical trials.