Repurposing Bazedoxifene for chemoprevention in pre-invasive pancreatic cancer IPMN

Precancerous lesions of pancreatic ductal adenocarcinoma (PDAC) called pancreatic intraductal papillary mucinous neoplasms (IPMN) can be detected radiographically, but monitoring and identifying patients who can benefit from surgical intervention before the development of malignant tumor has been an immense challenge in the management of patients with IPMN. Here we propose to investigate the feasibility of repurposing FDAapproved Bazedoxifene as a chemopreventive therapy for patients with IPMN in preclinical models, which may complement and improve the current care for these patients who are at high-risk for developing PDAC. Using unbiased computational and chemical screens, we have previously identified Bazedoxifene as a novel IL-6 signaling antagonist that can directly bind to GP130, a common component of IL-6 receptor complex. IL6/STAT3 is a vital oncogenic signaling axis that promotes pancreatic tumorigenesis. Elevated IL-6 level is associated with inflammation, aging, and poor prognosis and metastasis in pancreatic cancer patients. More recently, IL-6 secretion stimulated by IL-1-NFkB-JAK/STAT signaling is implicated in activating tumorpromoting inflammatory cancer associated fibroblast cells (iCAF). While inhibition of IL-6 and STAT3 to suppress PDAC has been pursued previously, here we propose to explore the uncharted efficacy of Bazedoxifene (a well-tolerated FDA-approved medication that is prescribed for osteoporosis prevention and can be taken orally) as a chemopreventive measure for patients who are identified as high-risk for developing PDAC, specifically those with detectable premalignant IPMN. To test our novel hypothesis that repurposing Bazedoxifene for chemoprevention would block IPMN progression to PDAC via inhibition of IL-6 signaling, we will 1) use 3D organoids derived from our unique mouse model for IPMN and from surgically resected IPMNs from patients to evaluate the functional and molecular impacts of Bazedoxifene as a chemopreventive agent on epithelial cells (Aim 1); 2) use our IPMN mouse model and orthotopically implanted murine and human IPMN 3D organoids to investigate the efficacy of Bazedoxifene as a chemopreventive therapy in vivo (Aims 1 & 2); 3) to investigate if Bazedoxifene also affects the stromal components, specifically the activation of quiescent fibroblast cells and the interconvertibility between CAF subtypes in vitro and in vivo (Aims 1 & 2). And lastly 4) since our knowledge of IL-6, metabolic alterations, CAF subtypes in pancreatic tumorigenesis has been gathered majorly from premalignant PanIN and invasive PDAC, to address this gap in knowledge, we will also compare and contrast IPMN organoids with PanIN and PDAC organoids to advance our understanding of the understudied IPMN (Aims 1 & 2). The success of our application will be transformative to clinical care of patients with IPMN and may be applicable to other known high-risk groups (i.e. patients with chronic pancreatitis, familial mutations, diabetes) for pancreatic cancer.