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

基本信息

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
项目类别：
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

项目摘要

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/摘要胰腺导管腺癌（PDAC）的癌性病变，称为胰腺内乳头状乳头状乳头状乳头瘤菌可以在射线照相上检测到粘液性肿瘤（IPMN），但可以监测和识别可以的患者在发生恶性肿瘤之前受益于手术干预措施是一个巨大的挑战在IPMN患者的管理中。在这里，我们建议调查重新利用FDA-的可行性批准的Bazedoxifene作为临床前模型中IPMN患者的化学预防疗法对于这些高风险开发PDAC的患者的补充并改善了当前的护理。使用公正的计算和化学筛选，我们先前已将Bazedoxifene鉴定为一种新颖 IL-6信号拮抗剂可以直接与IL-6受体复合物的常见成分GP130结合。 il- 6/STAT3是一个重要的致癌信号轴，可促进胰腺肿瘤发生。升高的IL-6级是胰腺癌患者的炎症，衰老和预后不良和转移相关。更多的最近，IL-6由IL-1-NFKB-JAK/STAT信号刺激的分泌与激活肿瘤有关促进炎症性癌症相关的成纤维细胞（ICAF）。而抑制IL-6和STAT3对抑制PDAC以前已被追求，我们在这里建议探索未知的功效 Bazedoxifene（一种耐受性良好的FDA批准药物，用于预防骨质疏松症和可以口服）作为一种化学预防措施，适用于被确定为高危的患者 PDAC，特别是那些具有可检测到预先验证的IPMN的PDAC。为了测试我们的新假设，即重新利用Bazedoxifene进行化学预防将阻止IPMN 通过抑制IL-6信号传导的进展到PDAC，我们将使用源自我们独特的3D类器官 IPMN的小鼠模型以及来自患者的手术切除的IPMN，以评估功能和 Bazedoxifene作为上皮细胞的化学预防剂的分子影响（AIM 1）； 2）使用我们的IPMN 小鼠模型和原位植入的鼠和人IPMN 3D器官研究的功效 Bazedoxifene作为体内化学预防疗法（AIMS 1＆2）； 3）调查bazedoxifene是否也影响基质成分，特别是静止成纤维细胞的激活和互通度在体外和体内CAF亚型之间（目标1和2）。最后是4）自我们了解IL-6的新陈代谢以来改变胰腺肿瘤发生的CAF亚型已主要是从Panin panin中收集的和Invasive PDAC，为了解决这一知识的差距，我们还将将IPMN类器官进行比较和对比 Panin和PDAC类器官可以提高我们对研究不足的IPMN的理解（目标1和2）。我们应用的成功将转变为IPMN患者的临床护理，可能是适用于其他已知的高危组（即慢性胰腺炎患者，家族突变，糖尿病）用于胰腺癌。