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：
8891386
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 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8891386
关键词：
Address Adenomatous Polyposis Coli Affinity Agonist American Anthelmintics Automobile Driving Beds Binding Biochemical Biological Biological Assay Biological Availability Biological Markers 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 Health 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 investigation clinical practice colon cancer cell line colon cancer patients design drug discovery embryo tissue improved in vivo inhibitor/antagonist innovation insight metastatic colorectal migration neoplastic cell novel novel strategies pre-clinical programs receptor receptor downregulation screening self-renewal small molecule targeted treatment 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/ß-catenin signaling via a novel mechanism involving internalization of Frizzled receptors and downregulation of Dishevelled and ß-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 ß-catenin. Importantly, niclosamide also inhibited Wnt/ß-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/ß-catenin inhibitors. Thus accelerate the translational application of niclosamide and its derivatives to improve patient survival.

描述（由适用提供）：Wnt信号转导途径，以细胞增殖，迁移，自我更新和存活而闻名，在许多类型的癌症中，尤其是结直肠癌（CRC），在该途径中激活突变发生在多种类型的癌症中。结果，抑制途径的药物是新一代创新治疗剂的基础。不幸的是，存在一个差距，可以用小型药物样分子靶向途径，这是发现该途径中靶向缺陷的药物的障碍。作为我们的床到床层工作的一部分，我们最近报道了FDA批准的药物烟酰胺通过一种新型机制抑制Wnt/ß-catenin信号传导，涉及毛线受体的内在化以及偶然的和β-catenin的下调。随后的研究表明，烟酰胺有望治疗大肠癌。具体而言，我们证明烟酰胺有选择地抑制结直肠癌细胞系和新鲜切除的人类结肠直肠肿瘤的肿瘤细胞增殖，包括含有APC和β-catenin突变的细胞。重要的是，烟酰胺还抑制了体内的Wnt/ß-catenin信号传导和结直肠肿瘤的生长，而小鼠Xenograpony模型中没有明显的毒性迹象。基于我们的发现，正在开发拟议的临床试验，其中在结肠镜检查之前，将在组织化学阶段进行组织化学评估烟酰胺的Wnt抑制活性。鉴于生化靶标的长期努力和差距可容纳药物发现，因此，FDA批准的药物烟酰胺抑制了该途径的发现非常重要，并提供了开发创新临床药物的机会。尽管如此，重新利用烟酰胺来治疗转移性CRC可能会受到其驱虫作用机理和次优的全身生物利用度的限制。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的鉴定提供了改善CRC治疗的潜力。我们的工作导致了以下假设：烟酰胺和优化的衍生物调节Wnt信号传导对治疗CRC很有用，并且通过结合可以探索可以探索药物发现的特定蛋白质靶标的抑制作用。该提案的目的是确定目标并定义烟酰胺介导的WNT信号抑制的机制，以便用烟酰胺为临床试验设计提供信息，并以适当的PK特性开发出更具潜力和选择性的最佳WNT信号抑制剂，以供将来的临床研究。该提案的具体目的是：（1）定义结构活动烟酰胺的关系（SAR）驱动Wnt抑制活性，并确定WNT信号的更多潜力和选择性抑制剂；（2）描述烟酰胺介导的Wnt信号抑制的分子机制，并鉴定烟酰胺的分子靶标；（3）确定新型烟酰胺衍生物在体内的肿瘤抑制作用。该提案的资金将使我们能够确定生物学靶标，并确定抑制剂，以在发现Wnt/ß-catenin抑制剂时克服临床研究的进展。这加速了烟酰胺及其衍生物的转化应用，以改善患者的生存。