Repurposing Bazedoxifene for chemoprevention in pre-invasive pancreatic cancer IPMN

项目总结/摘要 胰腺导管腺癌（PDAC）的癌前病变称为胰腺导管内乳头状 粘液性肿瘤（IPMN）可以通过放射学检查发现，但监测和识别可以 在恶性肿瘤发展之前进行手术干预是一个巨大的挑战 IPMN患者的管理。在这里，我们建议研究重新利用FDA的可行性- 在临床前模型中，批准了Bazedoxifene作为IPMN患者的化学预防治疗， 补充和改善目前对这些有发展PDAC高风险的患者的护理。 使用无偏的计算和化学筛选，我们以前已经确定了Bazedoxifene作为一种新的 IL-6信号传导拮抗剂，可直接结合GP 130，GP 130是IL-6受体复合物的共同组分。白介素- 6/STAT 3是促进胰腺肿瘤发生的重要致癌信号传导轴。IL-6水平升高 与胰腺癌患者的炎症、衰老、预后差和转移有关。更 最近，由IL-1-NFkB-JAK/STAT信号刺激的IL-6分泌涉及激活肿瘤， 促进炎性癌症相关成纤维细胞（iCAF）。当抑制IL-6和STAT 3时， 抑制PDAC以前一直在追求，在这里，我们建议探索未知的功效， Bazedoxifene（一种耐受性良好的FDA批准的药物，用于预防骨质疏松症， 可以口服）作为被确定为高风险发展的患者的化学预防措施 PDAC，特别是那些可检测到癌前IPMN的患者。 为了验证我们的新假设，即重新利用Bazedoxifene进行化学预防可以阻断IPMN 通过抑制IL-6信号传导进展到PDAC，我们将1）使用源自我们独特的 用于IPMN的小鼠模型和来自患者的手术切除的IPMN，以评价功能和 Bazedoxifene作为化学预防剂对上皮细胞的分子影响（目的1）; 2）使用我们的IPMN 小鼠模型和原位植入的鼠和人IPMN 3D类器官，以研究 Bazedoxifene作为体内化学预防治疗（目的1和2）; 3）研究Bazedoxifene是否也影响 基质成分，特别是静止成纤维细胞的活化和相互转化 CAF亚型之间的体外和体内（目的1和2）。最后4）由于我们对IL-6的了解， 胰腺肿瘤发生中的CAF亚型主要来自癌前PanIN， 和侵入性PDAC，为了解决这一知识差距，我们还将比较和对比IPMN类器官与 PanIN和PDAC类器官，以促进我们对未充分研究的IPMN的理解（目标1和2）。 我们应用的成功将对IPMN患者的临床护理产生变革性影响， 适用于其他已知的高风险人群（即慢性胰腺炎、家族性突变、糖尿病患者） 治疗胰腺癌

PROJECT SUMMARY/ABSTRACT 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 FDA- approved 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. IL- 6/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 tumor- promoting 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.