Mechanisms of Sensitivity to Cell Cycle Checkpoint Kinase Inhibitors

对细胞周期检查点激酶抑制剂敏感的机制

基本信息

批准号：
8633002
负责人：
ALAN R EASTMAN
金额：
$ 28.96万
依托单位：
DARTMOUTH COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-10 至 2018-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8633002
关键词：
7-Hydroxystaurosporine Address Antimetabolites Antineoplastic Agents Binding Bioavailable Biological Markers Cancer Therapy Evaluation Program Cell Cycle Arrest Cell Cycle Checkpoint Cell Line Cell Survival Cells Chemicals Cisplatin Clinical Clinical Trials Conduct Clinical Trials DNA DNA Damage Defect Development Dissection Drug Administration Schedule Drug Combinations Drug Delivery Systems Drug Targeting Evolution FDA approved Funding Genes Goals Human Human Cell Line Incubated Inhibitory Concentration 50 Investigation Malignant Epithelial Cell Mediating Medicine Orosomucoid Outcome Patients Pharmaceutical Preparations Phase I Clinical Trials Phosphotransferases Plasma Recovery Regulation Research Resistance Therapeutic Time Translations Tumor Cell Line Variant Xenograft Model cell killing design experience gemcitabine human CHEK1 protein hydroxyurea improved inhibitor/antagonist irinotecan kinase inhibitor neoplastic cell pre-clinical prevent programs public health relevance repaired research study response tumor tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): Many anticancer drugs target DNA resulting in activation of cell cycle checkpoints, arrest of proliferation, and repair, the consequence of which is recovery and survival of the tumor cells. Current efforts to enhance tumor cell killing include combining anticancer agents with inhibitors of DNA checkpoints. Chk1 has been identified as a critical kinase for cell cycle arrest and many inhibitors are currently in preclinical and clinical development; the current studies focus on the Chk1 inhibitor MK-8776. Recent results have identified a second critical function of Chk1 whereby it prevents the collapse of stalled replication forks. Accordingly, Chk1 inhibitors can dramatically sensitize cells to antimetabolites such as hydroxyurea and gemcitabine. Recently we discovered that stalled replication forks evolve to become more Chk1 dependent with time. This is critical to the development of Chk1 inhibitors as it impacts the timing of drug delivery in clinical trials. An additional observation s that some cell lines are hypersensitive to MK-8776 alone while others are completely resistant. The hypersensitive cell lines also require much less MK-8776 to sensitize them to hydroxyurea or gemcitabine. Accordingly, we hypothesize that a subset of tumors exist that will be highly responsive to the combination of MK-8776 plus either hydroxyurea or gemcitabine. This proposal will assess the variation in response to these drugs across a panel of cell lines and dissect the underlying mechanisms. The specific aims will 1) define the mechanism(s) for differential sensitivity of human tumor cell lines to MK-8776 as a single agent; 2) define the critical step(s) that occur at stalled replication forks that render them more Chk1 dependent with time; and 3) confirm the differential response of human cell lines when grown as xenograft tumors. In addition to establishing the underlying mechanisms, this research will define the optimum schedule of drug administration and biomarkers that can identify patients whose tumors are most likely to respond. This information will be critical for the design of clinical trils and selection of appropriate patients to treat.

描述（由申请人提供）：许多抗癌药物靶向DNA，导致细胞周期检查点激活，停止增殖和修复，其结果是肿瘤细胞的恢复和存活。当前增强肿瘤细胞杀伤的努力包括将抗癌剂与DNA检查点的抑制剂相结合。 CHK1已被确定为细胞周期停滞的关键激酶，许多抑制剂目前都处于临床前和临床状态发展;当前的研究集中于CHK1抑制剂MK-8776。最近的结果已经确定了CHK1的第二个关键功能，从而防止了停滞的复制叉的崩溃。因此，CHK1抑制剂可以显着使细胞对抗代谢物敏感例如羟基脲和吉西他滨。最近，我们发现停滞的复制叉进化为随着时间的流逝而变得更加依赖CHK1。这对于CHK1抑制剂的发展至关重要，因为它会影响临床试验中的药物输送时间。另外的观察结果是，某些细胞系对MK-8776高度敏感，而另一些细胞系完全抗性。高度敏感的细胞系还需要更少的MK-8776才能使其对羟基脲或吉西他滨敏感。因此，我们假设存在的一部分肿瘤将对MK-8776加羟基脲或吉西他滨的组合有很高的反应。该建议将评估跨细胞系中对这些药物的响应变化，并剖析潜在的机制。具体目的将1）定义人类肿瘤细胞系对MK-8776的差异敏感性的机制； 2）定义在停滞的复制叉处发生的关键步骤，从而使它们更多地依赖于时间； 3）确认当生长为异种移植肿瘤时，人类细胞系的差异反应。除了建立潜在的机制外，这项研究还将定义药物管理和生物标志物的最佳时间表，这些时间表可以鉴定肿瘤最有可能反应的患者。这些信息对于设计临床三LIL和选择适当的患者进行治疗至关重要。