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：
9321593
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 2019-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9321593
关键词：
Address Adenomatous Polyposis Coli Affinity Agonist American Anthelmintics Automobile Driving Beds Binding Biochemical Biological Biological Assay Biological Availability 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 Structure Structure-Activity Relationship Therapeutic Agents Toxic effect WNT Signaling Pathway Work Xenograft Model base bench to bedside beta catenin 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 mutational status neoplastic cell novel novel strategies patient biomarkers pre-clinical programs public health relevance receptor receptor downregulation screening self-renewal small molecule inhibitor targeted agent 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。超过 80% 的散发性结直肠癌中存在这种通路，因此，抑制该通路的药物作为新一代创新治疗药物的基础而备受追捧，但遗憾的是，其靶向能力存在差距。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抑制 Wnt/ß-。连环蛋白信号传导通过一种涉及卷曲受体内化和 Disheveled 和 β-连环蛋白下调的新机制进行。随后的研究表明，氯硝柳胺有望选择性地治疗结直肠癌。抑制结直肠癌细胞系和新切除的人结直肠肿瘤（包括含有 APC 和 ß-catenin 突变的细胞）的肿瘤细胞增殖。重要的是，氯硝柳胺还抑制体内 Wnt/ß-catenin 信号传导和结直肠肿瘤生长，且在体内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，其中将在息肉中对氯硝柳胺的 Wnt 抑制活性进行组织化学评估。鉴于长期的努力和药物发现的生化靶点的差距，FDA 批准的药物氯硝柳胺抑制该途径的发现非常重要，并为开发创新的临床药物提供了机会。重新利用氯硝柳胺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，因此需要鉴定具有更好效力、选择性和药代动力学特性的生化靶点和抑制剂。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。该提议的目的是确定氯硝柳胺介导的 Wnt 信号传导抑制的靶点并定义机制，以便为氯硝柳胺的临床试验设计提供信息，并为未来开发具有适当 PK 特性的更有效、选择性最佳的 Wnt 信号抑制剂该提案的具体目标是： (1) 定义结构-活性。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) 描述氯硝柳胺介导的 Wnt 信号传导抑制的分子机制，并确定氯硝柳胺的分子靶标；）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，以推进临床研究以克服发现中的障碍。从而加速氯硝柳胺及其衍生物的转化应用，以提高患者的生存率。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Perhexiline promotes HER3 ablation through receptor internalization and inhibits tumor growth.

Perhexiline 通过受体内化促进 HER3 消融并抑制肿瘤生长。

DOI：
发表时间：
2015-02-15
期刊：
影响因子：
0
作者：
Ren, Xiu;Wang, Jiangbo;Osada, Takuya;Mook Jr, Robert A;Morse, Michael A;Barak, Larry S;Lyerly, Herbert Kim;Chen, Wei
通讯作者：
Chen, Wei

Niclosamide: Beyond an antihelminthic drug.

氯硝柳胺：超越抗蠕虫药。