Targeting the MYC Oncogene with CDK Inhibitors

使用 CDK 抑制剂靶向 MYC 癌基因

基本信息

批准号：
8641666
负责人：
ANDREI GOGA
金额：
$ 34.17万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-04-19 至 2017-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8641666
关键词：
Acute Address Alleles Apoptosis Apoptotic Automobile Driving BCL2 gene BCL2L11 gene BIM Bcl-2-binding protein BIRC5 gene Biological CDC2 Protein Kinase CDK2 gene Cell Cycle Cell Cycle Inhibition Cell Death Cell Proliferation Cell Survival Cell physiology Cells Cessation of life Clinical Trials Cyclin-Dependent Kinase 4 Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Development Down-Regulation Enzymes Eukaryotic Cell Event Family Family member Genetic Genetic Transcription Goals Human Individual Investigation Knowledge Lead Lymphoma Malignant Neoplasms Malignant neoplasm of liver Mammalian Cell Mammary Neoplasms Mediating MicroRNAs Mitotic Mitotic spindle Modeling Molecular Molecular Target Mus Mutation Normal Cell Normal tissue morphology Oncogenes Oncogenic Pathway interactions Phase Phosphorylation Phosphotransferases Play Proliferating Protein Kinase Proteins Regulation Role Series Site Specificity Testing Therapeutic Time Transgenic Mice Translations Up-Regulation Work analog attenuation base cancer cell cancer therapy cell killing cellular engineering chemical genetics clinical practice improved in vivo inhibitor/antagonist innovation killings malignant breast neoplasm mouse model neoplastic neoplastic cell new therapeutic target novel novel therapeutics overexpression prevent programs public health relevance receptor small molecule survivin synthetic biology therapeutic target transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): The promise of molecular targeted therapy for cancer is to provide selective killing of tumor cells while sparing normal cells. Targeted therapy, however, requires that the oncogenic pathways activated in tumor cells can be defined, and that selective inhibitors can be found to abrogate these pathways. One major limitation to targeted therapeutic approaches is that many oncogenic pathways, especially those involving transcription factors, cannot be directly inhibited with small molecule compounds. An alternative approach is to use small molecule inhibitors that target basic cellular processes, such as the cell cycle, which merely arrest normal cells, but which in combination with activation of particular oncogenic pathways result in synthetic-lethal combinations. Cyclin-dependent kinases (CDKs) are a conserved family of protein kinases that play a central role in regulating the eukaryotic cell cycle. CDK1 and CDK2 are thought to be particularly important for driving the major cell cycle events in normal and neoplastic mammalian cells and these kinases might therefore be important targets for cancer therapy. The overall hypothesis that is being tested is whether inhibition of different CDKs can result in selective killing of tumor versus normal cells. (1) We seek to determine the genetic context in which cells are rendered especially sensitive to CDK inhibitors, resulting in cell death or another abortive cell cycle program. (2) We seek to determine how MYC oncogene over- expression sensitizes to cell death following CDK1 inhibition. (3) We seek to understand the molecular basis for cell death induced by CDK inhibition. To accomplish our goals we will utilize two complementary approaches to address this question. Both conventional small-molecule CDK inhibitors as well as a chemical-genetic approach will be employed to identify the genetic context in which CDK inhibitors may prove to be useful therapeutics. Our hypothesis, if confirmed, will significantly improve our understanding of how CDK inhibitors may be useful to target specific oncogenic pathways and should lead to novel therapeutics for cancer.

描述（由申请人提供）：分子靶向治疗癌症的承诺是在避免正常细胞的同时选择性地杀死肿瘤细胞。但是，有针对性的治疗要求可以定义在肿瘤细胞中激活的致癌途径，并且可以发现选择性抑制剂消除这些途径。靶向治疗方法的一个主要局限性是，许多致癌途径，尤其是涉及转录因子的途径，不能用小分子化合物直接抑制。另一种方法是使用针对基本细胞过程的小分子抑制剂，例如细胞周期，仅会阻止正常细胞，但与特定的致癌途径的激活结合起来会导致合成的致死组合。细胞周期蛋白依赖性激酶（CDKS）是一种保守的蛋白激酶家族，在调节真核细胞周期中起着核心作用。 CDK1和CDK2被认为对于在正常和肿瘤哺乳动物细胞中驱动主要细胞周期事件特别重要，因此这些激酶可能是癌症治疗的重要靶标。正在测试的总体假设是，抑制不同CDK的抑制是否会导致肿瘤与正常细胞的选择性杀死。（1）我们试图确定细胞对CDK抑制剂特别敏感的遗传环境，从而导致细胞死亡或其他流产细胞周期程序。（2）我们试图确定Myc癌基因在CDK1抑制后如何过度表达对细胞死亡敏感。（3）我们试图了解CDK抑制引起的细胞死亡的分子基础。为了实现我们的目标，我们将利用两种补充方法来解决这个问题。将采用常规的小分子CDK抑制剂以及一种化学遗传学方法来确定CDK抑制剂可能被证明是有用的疗法的遗传环境。如果得到证实，我们的假设将显着提高我们对CDK抑制剂如何对靶向特定致癌途径有用的理解，并应导致癌症的新型治疗方法。