Targeting the MYC Oncogene with CDK Inhibitors

描述（申请人提供）：癌症分子靶向治疗的前景是选择性杀死肿瘤细胞，同时保留正常细胞。然而，靶向治疗需要确定肿瘤细胞中激活的致癌途径，并找到选择性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那些，不能用小分子化合物直接抑制。另一种方法是使用靶向基本细胞过程（如细胞周期）的小分子抑制剂，其仅阻止正常细胞，但与特定致癌途径的激活组合导致合成-致死组合。细胞周期蛋白依赖性激酶（Cyclin-dependent kinases，CDKs）是一个保守的蛋白激酶家族，在真核细胞周期调控中发挥重要作用。CDK 1和CDK 2被认为对于驱动正常和肿瘤性哺乳动物细胞中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是否可以导致选择性杀死肿瘤细胞而不是正常细胞。(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个流产的细胞周期程序。(2)我们试图确定MYC癌基因的过度表达如何对CDK 1抑制后的细胞死亡敏感。(3)我们试图了解CDK抑制诱导细胞死亡的分子基础。为了实现我们的目标，我们将利用两种互补的方法来解决这个问题。传统的小分子CDK抑制剂以及化学遗传学方法将用于鉴定CDK抑制剂可能被证明是有用的治疗剂的遗传背景。我们的假设，如果得到证实，将显着提高我们的理解如何CDK抑制剂可能是有用的靶向特定的致癌途径，并应导致新的治疗癌症。 公共卫生相关性：正常的细胞增殖需要通过涉及多种调节酶的细胞周期的有序进展。相反，癌细胞不适当地增殖并且没有结束，导致肿瘤块。由于肿瘤细胞不适当地增殖，精确抑制细胞周期可能导致肿瘤细胞死亡，而正常细胞可能幸免。该提案的目标是确定选择性抑制细胞周期调节酶（称为细胞周期蛋白依赖性激酶（CDK））是否可以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，通过精确抑制细胞分裂周期来靶向具有特定遗传变化的肿瘤细胞。

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.