Repurposing Bazedoxifene for chemoprevention in pre-invasive pancreatic cancer IPMN

重新利用巴多昔芬对浸润前胰腺癌进行化学预防 IPMN

• 批准号: 10540747
• 负责人: Iok In Christine Chio
• 金额: $ 18.35万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-14 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10540747
• 关键词: 3-Dimensional; Address; Affect; Age; Aging; Binding; Cancer Etiology; Caring; Cell secretion; Cells; Cessation of life; Chemicals; Chemoprevention; Chemopreventive Agent; Chronic; Clinical; Clinical Trials; Complement; Complex; Data; Development; Diabetes Mellitus; Duct (organ) structure; Effectiveness; Elderly; Epithelial Cells; Epithelium; Estrogen Receptors; Estrogens; Excision; FDA approved; Fibroblasts; Genetically Engineered Mouse; Growth; Guidelines; Health Benefit; Heterogeneity; Histologic; Homeostasis; Human; IL-6 inhibitor; IL6 Signaling Pathway; IL6ST gene; Implant; In Vitro; Induction of Apoptosis; Inflammation; Inflammatory; Interleukin 6 Receptor; Interleukin-1; Interleukin-6; Knowledge; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Metabolic; Metastatic Neoplasm to the Liver; Modeling; Molecular; Molecular Analysis; Molecular Profiling; Monitor; Morbidity - disease rate; Mucinous Neoplasm; Mus; Mutation; NF-kappa B; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Oral; Organoids; Osteoporosis prevention; Oxidation-Reduction; Pancreas; Pancreatic Ductal Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Papillary; Pathway interactions; Patient Care; Patients; Pharmaceutical Preparations; Phenotype; Phosphorylation; Play; Postmenopause; Pre-Clinical Model; Preventive; Preventive measure; Preventive therapy; Preventive treatment; Prognosis; Property; Proteomics; Publishing; Research Subjects; Resectable; Resected; Risk Factors; Role; STAT3 gene; Safety; Serum; Signal Pathway; Signal Transduction; Survival Rate; Testing; Translating; Tumor Promotion; Woman; antagonist; attenuation; cancer invasiveness; chronic pancreatitis; clinical care; clinical practice; cytokine receptor gp130; efficacy evaluation; high risk; high risk population; implantation; improved; in vivo; insight; mouse model; neoplastic cell; novel; pancreatic cancer cells; pancreatic cancer patients; pancreatic ductal adenocarcinoma cell; pancreatic neoplasm; pancreatic stellate cell; pancreatic tumorigenesis; pre-clinical; premalignant; prevent; promoter; protein protein interaction; radiological imaging; response; senescence; success; tumor; tumor growth; tumor progression; tumorigenic

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.

项目概要/摘要 胰腺导管腺癌 (PDAC) 的癌前病变称为胰腺导管内乳头状病变 粘液性肿瘤（IPMN）可以通过放射线检查来检测，但监测和识别可以 在恶性肿瘤发生之前从手术干预中获益一直是一个巨大的挑战 IPMN 患者的管理。在此，我们建议调查 FDA 重新利用的可行性—— 在临床前模型中批准巴多昔芬作为 IPMN 患者的化学预防疗法，这可能 补充和改善目前对这些 PDAC 高风险患者的护理。 使用公正的计算和化学筛选，我们之前已将巴多昔芬确定为一种新型药物 IL-6 信号传导拮抗剂，可直接与 IL-6 受体复合物的常见成分 GP130 结合。白细胞介素- 6/STAT3 是促进胰腺肿瘤发生的重要致癌信号轴。 IL-6 水平升高是 与胰腺癌患者的炎症、衰老、不良预后和转移有关。更多的 最近，IL-1-NFkB-JAK/STAT 信号传导刺激的 IL-6 分泌与激活肿瘤相关 促进炎症性癌症相关成纤维细胞（iCAF）。同时抑制 IL-6 和 STAT3 抑制 PDAC 之前一直在追求，在这里我们建议探索未知的功效 巴多昔芬（一种经 FDA 批准的耐受性良好的药物，用于预防骨质疏松症和 可以口服）作为一种化学预防措施，用于被确定为患有该病的高风险患者 PDAC，特别是那些可检测到的癌前 IPMN。 为了检验我们的新假设，即重新利用巴多昔芬进行化学预防会阻断 IPMN 通过抑制 IL-6 信号传导进展为 PDAC，我们将 1) 使用源自我们独特的 3D 类器官 IPMN 小鼠模型和通过手术切除患者的 IPMN 来评估其功能和功能 巴多昔芬作为化学预防剂对上皮细胞的分子影响（目标 1）； 2）使用我们的IPMN 小鼠模型和原位植入的小鼠和人类 IPMN 3D 类器官来研究效果 巴多昔芬作为体内化学预防疗法（目标 1 和 2）； 3) 研究巴多昔芬是否也有影响 基质成分，特别是静止成纤维细胞的激活和相互转换性 体外和体内 CAF 亚型之间的差异（目标 1 和 2）。最后 4) 由于我们对 IL-6、代谢的了解 改变，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 PanIN 和 PDAC 类器官可增进我们对正在研究的 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，并且可能会 适用于其他已知的高危人群（即慢性胰腺炎、家族突变、糖尿病患者） 用于胰腺癌。