Targeting casein kinase 1-alpha for cancer therapy

项目摘要 结直肠癌是美国每年与癌症相关的死亡的第二大原因。尽管 我们对晚期结直肠癌分子基础的理解的最新进展， 化疗仍然是治疗的主要手段，疗效有限。激活WNT信号的突变 已知通路是大多数结直肠肿瘤的驱动因素，但没有有效的靶向治疗策略。 到目前为止，这种途径已经被开发出来。癌症患者全基因组功能缺失筛查的分析 细胞系的研究表明，依赖β-连环素生存的结直肠癌也容易患上 酪蛋白激酶1-α丢失(CK1A)。然而，CK1A的直接治疗靶向是未经证实的，而且它是 尚不清楚在结直肠癌中是否存在与β-连环蛋白信号的直接功能联系。这项建议 建立在初步发现的基础上，剖析结直肠癌中CK1A依赖的机制。我们将使用 互补的遗传学和药理学方法1)确定酪蛋白丢失之间的关系 2)在临床前模型中建立靶向CK1A的治疗效果， 3)阐明CK1A下游的磷酸化靶点。这些调查的结果是 有可能建立一种治疗结直肠癌的新方法。史蒂文·科塞洛博士的长期目标是 应用系统癌症易损性筛查的见解来推进癌症药物的发现 胃肠道癌症。科塞洛博士在达纳-法伯癌症研究所和布罗德研究所工作， 由癌症基因组学先驱托德·戈卢布博士和癌症生物学领军人物威廉·哈恩博士指导 和功能性基因筛查。由Nathanael Gray博士、Dr Nathanael Gray博士组成的专家职业咨询委员会。 Adam Bass和Brian Wolpin博士将在药物发现、疾病模型和 临床翻译。在导师的指导下，科塞洛博士制定了一项为期五年的全面培训 包括实验室培训、教学研究和科学社区参与的计划。

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.