Targeting casein kinase 1-alpha for cancer therapy

靶向酪蛋白激酶 1-α 进行癌症治疗

• 批准号: 10445233
• 负责人: Steven Muntean Corsello
• 金额: $ 20.65万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-06 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10445233
• 关键词: Address; Advanced Malignant Neoplasm; Advisory Committees; Affect; Attention; Bass; Binding Proteins; Biology; CSNK1A1 gene; Cancer Biology; Cancer Etiology; Cancer cell line; Caring; Cell Line; Cessation of life; Chemicals; Chemotherapy-Oncologic Procedure; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Dana-Farber Cancer Institute; Data; Dependence; Disease; Disease model; Event; Family member; Foundations; Genetic; Genetic Screening; Genetic Transcription; Goals; Growth; Impairment; Institutes; Investigation; Link; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Maps; Mentors; Mentorship; Methods; Molecular; Mutation; Nuclear; Organoids; Pathway interactions; Patients; Persons; Pharmacology; Phenotype; Phosphorylation; Phosphotransferases; Physiological; Play; Point Mutation; Pre-Clinical Model; Proteins; Reporting; Resistance; Role; Signal Transduction; Site-Directed Mutagenesis; Testing; Training; Treatment Efficacy; United States; WNT Signaling Pathway; Work; Xenograft Model; base; beta catenin; cancer cell; cancer genomics; cancer therapy; career; casein kinase; casein kinase I; clinical translation; colon cancer cell line; colon cancer patients; community engagement; cytotoxic; drug discovery; effective therapy; established cell line; experimental study; genome-wide; genome-wide analysis; in vivo; insight; kinase inhibitor; knock-down; laboratory experience; lenalidomide; loss of function; member; multidisciplinary; novel therapeutic intervention; phosphoproteomics; response; small hairpin RNA; small molecule inhibitor; therapeutic candidate; therapeutic target; therapeutically effective; treatment strategy; tumor; tumor growth

Project Summary Colorectal cancer is the second leading cause of cancer-related death in the United States annually. Despite recent advances in our understanding of the molecular underpinnings of advanced colorectal cancer, chemotherapy remains the mainstay of treatment, with limited efficacy. Mutations activating the WNT-signaling pathway are known to drive the majority of colorectal tumors, but no effective therapeutic strategies targeting this pathway have been developed to date. Analysis of genome-wide genetic loss of function screens in cancer cell lines has revealed that colorectal cancers that depend on beta catenin for survival are also vulnerable to loss of casein kinase 1-alpha (CK1A). Direct therapeutic targeting of CK1A is unproven, however, and it is unknown whether there is a direct functional link to beta catenin signaling in colorectal cancer. This proposal builds on preliminary findings to dissect the mechanism of CK1A dependence in colorectal cancer. We will use complementary genetic and pharmacologic approaches to 1) determine the relationship between loss of casein kinase and beta catenin activity, 2) establish the therapeutic efficacy of targeting CK1A in preclinical models, and 3) elucidate downstream phosphorylation targets of CK1A. Results of these investigations have the potential to establish a new treatment approach for colorectal cancer. Dr. Steven Corsello’s long-term goal is to apply insights from systematic cancer vulnerability screens to advance cancer drug discovery for the treatment of gastrointestinal cancers. Dr. Corsello, based at the Dana-Farber Cancer Institute and the Broad Institute, is mentored by Dr. Todd Golub, a pioneer in cancer genomics, and Dr. William Hahn, a leader in cancer biology and functional genetic screening. An expert career advisory committee consisting of Dr. Nathanael Gray, Dr. Adam Bass, and Dr. Brian Wolpin will provide additional mentorship in drug discovery, disease models, and clinical translation. With input from his mentors, Dr. Corsello has developed a comprehensive five-year training plan incorporating laboratory training, didactic studies, and scientific community engagement.

项目摘要 大肠癌是美国年度癌症相关死亡的第二大原因。尽管 我们对晚期结直肠癌分子基础的理解的最新进展， 化学疗法仍然是治疗的主要手段，效率有限。激活Wnt信号的突变 已知途径可以推动大多数结直肠肿瘤，但没有针对的有效治疗策略 迄今为止，该途径已经开发。分析癌症全基因组遗传损失的遗传丧失 细胞系表明，依赖β链氨酸蛋白蛋白生存的结直肠癌也很容易受到伤害 酪蛋白激酶1-α（CK1A）的丧失。 CK1A的直接治疗靶向尚未得到证实，这是 尚不清楚结直肠癌中是否存在与β链球菌信号传导的直接联系。这个建议 建立在初步发现的基础上，以剖析结直肠癌中CK1A依赖性的机制。我们将使用 完全遗传和药物方法1）确定病例丢失之间的关系 激酶和β链球菌活性，2）在临床前模型中建立靶向CK1A的治疗效率， 3）阐明CK1A的下游磷酸化靶标。这些调查的结果具有 为结直肠癌建立新的治疗方法的潜力。史蒂文·科塞罗（Steven Corsello）博士的长期目标是 应用系统的癌症脆弱性筛查中的见解，以促进治疗的癌症药物发现 胃肠道癌。 Dana-Farber癌症研究所和Broad Institute的Corsello博士是 由癌症基因组学的先驱托德·戈鲁布（Todd Golub）和癌症生物学领导者威廉·哈恩（William Hahn）的指导 和功能性遗传筛查。由Nathanael Gray博士组成的专业职业咨询委员会，博士。 亚当·巴斯（Adam Bass）和布莱恩·沃尔平（Brian Wolpin）博士将在药物发现，疾病模型和 临床翻译。在他的导师的意见下，科塞洛博士开展了全面的五年培训 计划纳入实验室培训，教学研究和科学社区参与。

项目成果

Structure-Based Design of Y-Shaped Covalent TEAD Inhibitors.

• DOI: 10.1021/acs.jmedchem.2c01548
• 发表时间: 2023-04-13
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Lu, Wenchao;Fan, Mengyang;Ji, Wenzhi;Tse, Jason;You, Inchul;Ficarro, Scott B.;Tavares, Isidoro;Che, Jianwei;Kim, Audrey Y.;Zhu, Xijun;Boghossian, Andrew;Rees, Matthew G.;Ronan, Melissa M.;Roth, Jennifer A.;Hinshaw, Stephen M.;Nabet, Behnam;Corsello, Steven M.;Kwiatkowski, Nicholas;Marto, Jarrod A.;Zhang, Tinghu;Gray, Nathanael S.
• 通讯作者: Gray, Nathanael S.