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.

项目摘要/摘要 称为胰腺导管内乳头状癌的胰腺导管腺癌癌前病变 粘液性肿瘤(IPMN)可以通过放射学检查发现，但监测和识别哪些患者可以 在恶性肿瘤发展之前接受手术干预一直是一个巨大的挑战 在IPMN患者的管理中。在这里，我们建议研究重新调整FDA用途的可行性- 在临床前模型中批准巴多昔芬作为IPMN患者的化学预防治疗，这可能 补充和改善目前对这些患有PDAC高危患者的护理。 利用无偏的计算和化学筛选，我们以前已经确定巴多昔芬是一种新的 IL-6信号拮抗剂，可直接与IL-6受体复合体的常见成分gp130结合。伊尔- 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、预后不良和转移有关。更多 最近，IL-1-NFkB-JAK/STAT信号刺激的IL-6分泌与激活肿瘤相关。 促进炎性癌症相关成纤维细胞(ICAF)。而对IL-6和STAT3的抑制作用 抑制PDAC之前一直在进行，在这里我们建议探索未知的疗效 巴多昔芬(一种耐受性良好的FDA批准的药物，用于预防骨质疏松症和 可以口服)作为一种化学预防措施，用于被确定为高危疾病的患者 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，即重新用于化学预防的巴多昔芬将阻断IPMN 通过抑制IL-6信号向PDAC发展，我们将1)使用来自我们独特的 建立小鼠IPMN模型和手术切除患者的IPMN，以评估其功能和功能 巴多昔芬作为化学预防药物对上皮细胞的分子影响(目标1)；2)使用我们的IPMN 小鼠模型及原位植入小鼠和人IPMN 3D有机化合物的疗效观察 巴多昔芬作为体内化学预防疗法(AIMS 1和2)；3)研究巴多昔芬是否也影响 间质成分，特别是静止的成纤维细胞的激活和相互转化 体外和体内CAF亚型之间的差异(目标1和2)。最后4)自从我们知道了IL-6，新陈代谢 胰腺癌前病变、CAF亚型在胰腺癌发生中的作用 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有机物和 Panin和PDAC有机化合物，以促进我们对未被研究的IPMN的理解(目标1和2)。 我们的成功应用将对IPMN患者的临床护理产生变革，并可能 适用于其他已知的高危人群(即慢性胰腺炎、家族性突变、糖尿病患者) 治疗胰腺癌。