Targeting Anaphase Catastrophe to Combat Lung Cancer

针对后期灾难来对抗肺癌

基本信息

批准号：
8800790
负责人：
ETHAN DMITROVSKY
金额：
$ 38.14万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8800790
关键词：
Anaphase Anchorage-Independent Growth Aneuploid Cells Aneuploidy Apoptosis Biological Biological Assay Biology Cancer Etiology Cancer Model Cancer cell line Cell Death Cell Line Cells Centrosome Cessation of life Chromosomal Instability Chromosome Segregation Chromosomes Clinical Collaborations Cyclin E Databases Daughter Defect Diploid Cells Dominant-Negative Mutation Engineering Epithelial Cells Exhibits Genetic Databases Genomic Instability Human In Vitro Individual KRAS2 gene Kinetics Learning Life Link Lung Malignant - descriptor Malignant neoplasm of lung Mediating Mediator of activation protein Medical Mitotic Mus Mutation Oncogenic Pathway interactions Patients Phosphorylation Preclinical Drug Evaluation Proteins Relative (related person)Resources Robotics Site Structure of parenchyma of lung Tissue Banking Tissue Banks Tissue Microarray Transgenic Mice Transgenic Organisms Transplantation United States National Institutes of Health Woman Work base cancer cell cancer prevention cancer therapy cell growth cellular imaging clinically relevant combat improved inhibitor/antagonist men mutant neoplastic neoplastic cell novel prevent public health relevance segregation tumor

项目摘要

DESCRIPTION (provided by applicant): Lung cancer is the most common cause of cancer death for both women and men. There is therefore a pressing need to improve lung cancer therapy and prevention. This is the subject of this new NIH R01 application in which we now seek to elucidate a previously unrecognized pathway that we found as clinically-tractable in combating lung cancer. Termed anaphase catastrophe, this is caused by targeting the cyclin E-Cdk2 pathway in aneuploidy cancer cells. Neoplastic cells are genetically unstable; strategies that target genome instability are attractive ways to disrupt tumor cell growth and potentially spare normal diploid cells. Chromosome instability (CIN) is genome instability via mitotic defects that increase chromosome mis-segregation. CIN is caused by extra centrosomes that disrupt bipolar spindle assembly needed for faithful chromosome segregation. We found that Cdk2 inhibition prevents centrosome clustering and forces chromosomes to segregate into multiple daughter cancer cells. This triggers apoptosis in aneuploid cells, including lung cancer cells, as will be studied here. Using a robotic cell-based drug screening platform linked to a genetic database, KRAS mutant lung cancer (representing an unmet medical need) cells were exquisitely sensitive to Cdk2 inhibition because they exhibit anaphase catastrophe and apoptosis. CP110 is a centrosome protein and direct Cdk2 phosphorylation target that regulates centrosome clustering. Our hypothesis is: CP110 is the centrosome protein responsible for anaphase catastrophe. Our interdisciplinary team has a long track record of productive collaboration. We have assembled for this work selective Cdk2 inhibitors, clinically-relevant transgenic cyclin E-driven and KRAS-driven mouse lung cancer models and their derived cell lines. A large human lung cancer cell line panel is available as is a paired normal- malignant lung tissue array linked to a clinical database. Our team will use these resources to interrogate these Specific Aims to: (1) learn if CP110 is the critical target of Cdk2 inhibition that antagonizs centrosome clustering and promotes multipolar anaphase to trigger lung cancer cell death; (2) elucidate whether CP110 is the critical mediator of Cdk2-dependent anti-neoplastic effects in lung cancer cells; and (3) establish the biological and clinical relevance of this work using clinically- predictive in vitro, transgenic, and normal-malignant lung tissue banks. Successful completion of these aims would provide a new way to confront lung cancer, the most common cause of cancer death for men and women. This would ultimately identify which lung cancer cases are amenable to Cdk2 inhibition.

描述（由申请人提供）：肺癌是男女癌症死亡的最常见原因。因此，需要提高肺癌疗法和预防的迫切需求。这是这项新的NIH R01应用程序的主题，我们现在试图阐明我们在打击肺癌时发现的先前未知的途径。这被称为后期灾难，这是由靶向过倍性癌细胞中的细胞周期蛋白E-CDK2途径引起的。肿瘤细胞在遗传上不稳定。靶向基因组不稳定性的策略是破坏肿瘤细胞生长并潜在避免正常二倍体细胞的有吸引力的方法。染色体不稳定性（CIN）是通过增加染色体错误分离的有丝分裂缺陷的基因组不稳定性。 CIN是由额外的中心体引起的，这些中心体破坏了忠实的染色体隔离所需的双极纺锤体组件。我们发现CDK2抑制作用可防止中心体聚类，并迫使染色体分离为多个子癌细胞。这会触发非整倍体细胞中的凋亡，包括肺癌细胞，如这里所研究。使用与遗传数据库相关的基于机器人细胞的药物筛查平台，KRAS突变肺癌（代表未满足的医疗需求）细胞对CDK2抑制非常敏感，因为它们表现出后期的灾难和凋亡。 CP110是一种转化中心体聚类的中心体蛋白和直接的CDK2磷酸化靶标。我们的假设是：CP110是导致后期灾难的中心体蛋白。我们的跨学科团队拥有长期的生产协作记录。我们已经为这项工作选择性CDK2抑制剂，临床上与转基因细胞周期蛋白E驱动和KRAS驱动的小鼠肺癌模型及其衍生细胞系组装。可以提供一个大型的人类肺癌细胞系面板，以及与临床数据库相关的配对正常恶性肺组织阵列。我们的团队将使用这些资源来询问这些特定目标：（1）了解CP110是否是CDK2抑制的关键目标，即拮抗contagonizs contrososem centrosome centrosome centrosome clustering并促进多极后期以触发肺癌细胞死亡；（2）阐明CP110是否是肺癌细胞中CDK2依赖性抗塑性作用的关键介体；（3）使用临床预测性的体外，转基因和正常恶性肺组织库建立这项工作的生物学和临床相关性。这些目标的成功完成将为面对肺癌的新方法，这是男性和女性癌症死亡的最常见原因。这最终将确定哪些肺癌病例可以受到CDK2抑制作用。