CDK Inhibition in Cancer

描述（由申请人提供）：了解细胞周期蛋白依赖性激酶（Cdks）的选择性抑制如何影响正常和肿瘤细胞的生长，可能会导致新的癌症治疗策略。Cdks是一个保守的丝氨酸/苏氨酸激酶家族，在调节真核细胞周期中起核心作用。Cdk2和Cdk1通常被认为分别控制脊椎动物细胞周期的S期和M期。它们在脊椎动物细胞中的确切功能一直难以确定，因为没有区分Cdk1和Cdk2的真正特异性抑制剂。Cdks在细胞周期进程中的重要作用使它们成为开发特异性抑制剂作为抗癌药物的极大兴趣的目标。肿瘤细胞发展出一个不受控制的细胞周期，这可能使它们的生长对Cdk抑制特别敏感。这提出了Cdk抑制可能导致肿瘤细胞的主要杀伤而保留正常细胞的可能性。目前还没有小鼠模型来验证特异性Cdk抑制在肿瘤发生中的作用。候选人的长期目标是了解正常细胞和肿瘤细胞如何对Cdk抑制作出反应，并应用这些知识来开发新的治疗癌症的策略。首先，我们将研究Cdk抑制在多种致癌基因转化的细胞中的作用。转基因小鼠肿瘤模型系统将培育出含有致癌基因的菌株，使细胞对Cdk抑制敏感。我们将测试Cdk抑制是否可以介导内源性肿瘤的显著消退，或防止肿瘤的新生发展。第二，生成可被可溶性小分子选择性抑制的Cdks突变体。第三，我们将确定与Cdk1和Cdk2抑制相关的精确细胞周期阻滞点和细胞后果。该候选人是一名内科科学家，目前正在进行博士后培训，他提议在加州大学旧金山分校的J. Michael Bishop和David Morgan指导下进行5年的研究。拟议的培训计划旨在为申请人准备在学术肿瘤科建立一个独立的实验室。

DESCRIPTION (provided by applicant): Understanding how selective inhibition of cyclin-dependent kinases (Cdks) affects normal and tumor cell growth may lead to novel treatment strategies for cancer. Cdks are a conserved family of serine/threonine kinases that serve a central role in regulating the eukaryotic cell cycle. Cdk2 and Cdk1 are generally thought to control the S and M phases of the vertebrate cell cycle, respectively. Their exact function in vertebrate cells has been difficult to define because there are no truly specific inhibitors that distinguish between Cdk1 and Cdk2. The essential role of Cdks in cell cycle progression makes them a target of great interest for the development of specific inhibitors as anti-cancer agents. Tumor cells develop a deregulated cell cycle that may render their growth especially sensitive to Cdk inhibition. This raises the possibility that Cdk inhibition may result in the predominant killing of tumor cells while sparing normal cells. Currently no murine model exists to validate the role of specific Cdk inhibition in developing tumors. The long-term goal of the candidate, and this proposal, is to understand how normal and tumor cells respond to Cdk inhibition and to apply this knowledge to develop new therapeutic strategies against cancer. First, we will examine the effect of Cdk inhibition in the context of cells transformed by a variety of oncogenes. Transgenic mouse tumor model systems will be bred to strains harboring oncogenes that render cells sensitive to Cdk inhibition. We will test if Cdk inhibition can mediate significant regression of endogenous tumor, or prevent de novo tumor development. Second, mutant forms of Cdks that can be selectively inhibited in vivo by soluble small molecules will be generated. Third, we will determine the precise cell cycle arrest points and cellular consequences associated with Cdk1 and Cdk2 inhibition. The candidate is a physician-scientist currently pursuing post-doctoral training who is proposing a 5-year mentored research experience with J. Michael Bishop and David Morgan at the University of California, San Francisco. The proposed training program is designed with the goal of preparing this applicant to establish an independent laboratory in an academic oncology department.