Inhibition of Wnt/B-Catenin Signaling in Colorectal Cancer Therapy

结直肠癌治疗中 Wnt/B-Catenin 信号传导的抑制

基本信息

批准号：
8578066
负责人：
WEI CHEN
金额：
$ 32.58万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-19 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8578066
关键词：
Address Adenomatous Polyposis Coli Affinity Agonist American Anthelmintics Automobile Driving Beds Binding Biochemical Biological Biological Assay Biological Availability Biological Markers Cancer Patient Cancer cell line Cell Proliferation Cells Chemical Structure Clinical Clinical Research Clinical Trials Clinical Trials Design Colon Carcinoma Colonoscopy Colorectal Cancer Colorectal Neoplasms Data Defect Disease Down-Regulation Drug Design Drug Kinetics Drug Targeting Elements Embryonic Development Enrollment FDA approved Funding Future Generations Genes Genetic Screening Goals Homeostasis Human Immunodeficient Mouse In Vitro Inherited Investments Lead Mediating Modeling Molecular Molecular Target Mus Mutation Pathway interactions Patients Pharmaceutical Preparations Phase Polyps Property Proteins Public Health Reagent Regulation Reporting Research Resected Running Signal Pathway Signal Transduction Signal Transduction Pathway Solutions Structure Structure-Activity Relationship Therapeutic Agents Toxic effect Work Xenograft Model Xenograft procedure base bench to bedside cancer cell cancer therapy cancer type chemical genetics clinical practice design drug discovery embryo tissue improved in vivo inhibitor/antagonist innovation insight metastatic colorectal migration neoplastic cell novel novel strategies pre-clinical programs public health relevance receptor receptor downregulation screening self-renewal small molecule tumor tumor growth

项目摘要

DESCRIPTION (provided by applicant): The Wnt signal transduction pathway, known for regulating genes involved in cell proliferation, migration, self- renewal, and survival, is dysregulated in many types of cancers, particularly colorectal cancer (CRC) where activating mutations in this pathway occur in over 80% of sporadic colorectal cancers. As a result, drugs that inhibit the pathway are highly sought-after as the basis of a new generation of innovative therapeutic agents. Unfortunately, a gap exists in the ability to target the pathway with small, drug-like molecules, a gap that is the barrier to discovering drugs targeting defects in this pathway. As part of our bed-to-bedside effort, we recently reported the FDA-approved drug niclosamide inhibits Wnt/?-catenin signaling via a novel mechanism involving internalization of Frizzled receptors and downregulation of Dishevelled and ?-catenin. Subsequent studies showed that niclosamide holds promise to treat colorectal cancer. Specifically, we demonstrated that niclosamide selectively inhibited tumor cell proliferation in colorectal cancer cell lines and freshly resected human colorectal tumors, including cells harboring mutations in APC and ?-catenin. Importantly, niclosamide also inhibited Wnt/?-catenin signaling and colorectal tumor growth in vivo without obvious signs of toxicity in mouse xenograft models. Based on our discovery, proposed clinical trials are being developed, in which the Wnt inhibitory activity of niclosamide in polyps will be evaluated histochemically after a run-in phase prior to colonoscopy. Given the long-standing efforts and gap in biochemical targets amenable to drug discovery, the finding that a FDA-approved drug niclosamide inhibits the pathway is highly significant and offers an opportunity to develop innovative clinical agents. Nonetheless, repurposing niclosamide to treat metastatic CRC may be limited by its anthelmintic mechanism of action and suboptimal systemic bioavailability. Identification of the biochemical target and inhibitors with better potency, selectivity and pharmacokinetic properties offer the potential to improve treatment of CRC. Our work led to the hypothesis that modulating Wnt signaling by niclosamide and optimized derivatives are useful to treat CRC and that inhibition occurs by binding a specific protein target that can be exploited for drug discovery. The objective of this proposal is to identify the target and define the mechanism of niclosamide-mediated inhibition of Wnt signaling in order to inform clinical trial designs with niclosamide, and to develop more potent and selective best-in-class Wnt signaling inhibitors with appropriate PK properties for future clinical studies. The specific aims of the proposal are to: (1) To define Structure-Activity Relationships (SAR) of niclosamide driving Wnt inhibitory activity and to identify more potent and selective inhibitors of Wnt signaling; (2) To delineate the molecular mechanism underlying niclosamide-mediated inhibition of Wnt signaling and to identify the molecular target of niclosamide; and (3) To determine the tumor inhibitory effect of novel niclosamide derivatives in vivo. Funding of this proposal will enable us to identify the biological target and identify inhibiors to progress toward clinical studies to overcome a barrier in the discovery of Wnt/?-catenin inhibitors. Thus accelerate the translational application of niclosamide and its derivatives to improve patient survival.

描述（由申请人提供）：Wnt 信号转导通路以调节参与细胞增殖、迁移、自我更新和存活的基因而闻名，但在许多类型的癌症中失调，特别是结直肠癌 (CRC)，其中激活了该通路中的突变。 80%以上的散发性结直肠癌中存在该途径。因此，抑制该途径的药物作为新一代创新治疗药物的基础而备受追捧。不幸的是，在用类似药物的小分子靶向该途径的能力方面存在差距，这一差距是发现针对该途径缺陷的药物的障碍。作为我们床边工作的一部分，我们最近报道了 FDA 批准的药物氯硝柳胺通过一种新机制抑制 Wnt/β-catenin 信号传导，该机制涉及卷曲受体的内化以及 Disheveled 和 β-catenin 的下调。随后的研究表明，氯硝柳胺有望治疗结直肠癌。具体来说，我们证明氯硝柳胺选择性抑制结直肠癌细胞系中的肿瘤细胞增殖，并且新鲜切除的人类结直肠肿瘤，包括含有 APC 和 β-连环蛋白突变的细胞。重要的是，氯硝柳胺还在体内抑制 Wnt/β-catenin 信号传导和结直肠肿瘤生长，而在小鼠异种移植模型中没有明显的毒性迹象。根据我们的发现，正在开展拟议的临床试验，其中将在结肠镜检查前的磨合期后对息肉中氯硝柳胺的 Wnt 抑制活性进行组织化学评估。鉴于药物发现的生化目标方面的长期努力和差距，FDA 批准的药物氯硝柳胺抑制该途径的发现非常重要，并为开发创新临床药物提供了机会。尽管如此，重新利用氯硝柳胺来治疗转移性结直肠癌可能会受到其驱虫作用机制和次优的全身生物利用度的限制。鉴定具有更好效力、选择性和药代动力学特性的生化靶标和抑制剂为改善结直肠癌的治疗提供了潜力。我们的工作提出了这样的假设：通过氯硝柳胺和优化的衍生物调节 Wnt 信号传导可用于治疗 CRC，并且通过结合可用于药物发现的特定蛋白质靶点来发生抑制。该提案的目的是确定氯硝柳胺介导的 Wnt 信号传导抑制的靶点并确定其机制，以便为氯硝柳胺的临床试验设计提供信息，并开发具有适当 PK 的更有效、选择性最佳的 Wnt 信号抑制剂未来临床研究的特性。该提案的具体目标是： (1) 定义结构-活动氯硝柳胺驱动 Wnt 抑制活性的关系 (SAR)，并鉴定更有效和选择性的 Wnt 信号传导抑制剂； (2) 阐明氯硝柳胺介导的Wnt信号抑制的分子机制，并确定氯硝柳胺的分子靶点； (3)确定新型氯硝柳胺衍生物的体内肿瘤抑制作用。该提案的资助将使我们能够确定生物靶点并确定抑制剂，以推进临床研究，克服发现 Wnt/β-连环蛋白抑制剂的障碍。从而加速氯硝柳胺及其衍生物的转化应用，提高患者生存率。