Targeting the MYC Oncogene with CDK Inhibitors

描述(申请人提供)：分子靶向治疗癌症的前景是在保留正常细胞的同时提供对肿瘤细胞的选择性杀伤。然而，靶向治疗要求能够定义在肿瘤细胞中激活的致癌途径，并且可以找到选择性的抑制剂来消除这些途径。靶向治疗方法的一个主要限制是许多致癌途径，特别是涉及转录因子的途径，不能直接用小分子化合物抑制。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，它只会阻止正常细胞，但与特定致癌途径的激活相结合，会导致合成-致死组合。细胞周期蛋白依赖性蛋白激酶(CDKs)是一类保守的蛋白激酶家族，在真核细胞周期调控中起着核心作用。CDK1和CDK2被认为对驱动正常和肿瘤哺乳动物细胞的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点。正在测试的总体假设是，抑制不同的CDK是否可以导致对肿瘤细胞的选择性杀伤而不是正常细胞。(1)我们试图确定细胞对CDK抑制剂特别敏感的遗传背景，导致细胞死亡或另一种流产的细胞周期程序。(2)研究CDK1抑制后MYC癌基因过度表达对细胞死亡的敏感性。(3)探讨CDK抑制诱导细胞死亡的分子基础。为了实现我们的目标，我们将利用两种相辅相成的办法来解决这个问题。传统的小分子CDK抑制剂以及化学-遗传学方法都将被用来确定CDK抑制剂可能被证明是有用的疗法的遗传背景。如果我们的假设得到证实，将显著提高我们对CDK抑制剂如何有助于靶向特定致癌途径的理解，并应导致癌症的新疗法。 与公共健康相关：正常的细胞增殖需要在细胞周期中有序地进行，其中涉及多种调节酶。相反，癌细胞不适当地无休止地增殖，导致肿瘤肿块。由于肿瘤细胞不适当地增殖，精确地抑制细胞周期可能会导致肿瘤细胞死亡，而正常细胞可能会幸免于难。这项建议的目的是确定选择性抑制细胞周期调节酶，即细胞周期蛋白依赖性蛋白激酶(CDKs)，是否会导致肿瘤细胞的停滞或死亡。从这些研究中获得的知识将有助于开发新的治疗方法，通过精确地抑制细胞分裂周期来针对具有特定基因变化的肿瘤细胞。

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. PUBLIC HEALTH RELEVANCE: Normal cellular proliferation requires an orderly progression through the cell cycle that involves multiple regulatory enzymes. In contrast, cancer cells proliferate inappropriately and without end resulting in a tumor mass. Since tumor cells proliferate inappropriately, precise inhibition of the cell cycle may lead to the death of tumor cells while normal cells may be spared. The goal of this proposal is to determine if selective inhibition of cell cycle regulatory enzymes, known as cyclin-dependent kinases (CDKs), can cause the arrest or perhaps death of tumor cells. The knowledge gained from these studies will facilitate the development of new therapeutics that target tumor cells with particular genetic changes by precisely inhibiting the cell division cycle.