Targeting Chk1 in Acute Myeloid Leukemia

 描述（由申请人提供）：2014年，美国将有超过14，000名成年人被诊断患有急性髓性白血病（AML）。标准疗法是阿糖胞苷（AraC）加蒽环类抗生素的组合。尽管这种治疗方案诱导了高缓解率，但约30%的成人AML对原发性化疗难治，超过50%的成人AML将复发并对其他治疗难治。因此，迫切需要开发更好的治疗AML或预防耐药疾病发展的疗法。 解决这一问题的一种方法是通过用小分子抑制剂靶向ATR-Chk 1信号通路中的核心参与者Chk 1来增强AraC的活性。该方法源于1）ATR-Chk 1信号传导途径的广泛的机制和临床前研究，其显示该途径保护白血病细胞免受AraC诱导的细胞毒性，以及2）小分子Chk 1抑制剂的开发，其目前处于临床试验中，并且在肿瘤疾病中显示出令人兴奋的活性，而不增加毒性，包括最近完成的AraC加Chk 1抑制剂的1期试验。 尽管取得了这一进展，但Chk 1的分子功能和Chk 1抑制AML的机制仍然知之甚少。此外，目前还不清楚为什么有些患者对这种疗法有反应，而另一些则没有。我们的中心假设是，通过了解AraC治疗的AML细胞中Chk 1的功能和调节，我们可以确定与Chk 1抑制剂反应相关的生物标志物，从而为有效开发和部署Chk 1抑制剂治疗AML和其他肿瘤铺平道路。 该提案的总体目标是确定Chk 1如何调节AraC治疗的AML细胞的存活，并确定Chk 1抑制如何促进细胞死亡，作为1）机械评价Chk 1功能的一种手段，以及2）确定潜在的生物标志物，这将有助于选择最有可能对Chk 1抑制剂治疗有反应的患者。有了这些信息，我们将准备好探索这些潜在的 生物标志物与正在进行的2期试验中对AraC+ Chk 1抑制剂的抗白血病反应相关。值得注意的是，这些研究代表了开发Chk 1抑制剂治疗的独特机会，因为2期试验是第一个在Chk 1抑制可能有益的疾病环境中使用高选择性Chk 1抑制剂的试验。重要的是，这些研究的成功将为AML和其他肿瘤疾病中Chk 1抑制剂的开发提供信息。

 DESCRIPTION (provided by applicant): Over 14,000 adults will be diagnosed with acute myeloid leukemia (AML) in the United Sates in 2014. The standard therapy is a combination of cytarabine (AraC) plus an anthracycline. Although this treatment regimen induces high rates of remission, approximately 30% of adult AML is refractory to primary chemotherapy, and over 50% will relapse and become refractory to additional therapies. Accordingly, there is a pressing need to develop better therapies that treat AML or prevent development of drug-resistant disease. One approach to this problem is to enhance the activity of AraC by targeting Chk1, a central participant in the ATR-Chk1 signaling pathway, with small molecule inhibitors. This approach stems from 1) extensive mechanistic and preclinical studies of the ATR-Chk1 signaling pathway showing that this pathway protects leukemia cells from cytotoxicity induced by AraC, and 2) the development of small molecule Chk1 inhibitors that are currently in clinical trials and that are showing exciting activity, without increased toxicity, in neoplastic diseases, including a recently completed Phase 1 trial of AraC plus a Chk1 inhibitor. Despite this progress, the molecular functions of Chk1 and the mechanistic consequences of Chk1 inhibition in AML remain poorly understood. Furthermore, it remains unclear why some patients respond to this therapy and others do not. Our central hypothesis is that by understanding the functions and regulation of Chk1 in AraC-treated AML cells we can identify biomarkers that associate with responses to Chk1 inhibitors, thus paving the way to effectively develop and deploy Chk1 inhibitors to treat AML and other neoplasms. The overarching goals of this proposal are to identify how Chk1 regulates survival of AML cells treated with AraC and determine how Chk1 inhibition contributes to cell death as a means to 1) mechanistically evaluate Chk1 function, and 2) identify potential biomarkers that will help select patients most likely to respond to Chk1 inhibitor therapy. With this information, we will then be poised to explore whether these potential biomarkers associate with antileukemic responses to AraC+Chk1 inhibitor in an ongoing Phase 2 trial. Notably, these studies represent a unique opportunity in the development of Chk1 inhibitor therapy because the Phase 2 trial is the first to use a highly selective Chk1 inhibitor i a disease setting in which Chk1 inhibition may be beneficial. Importantly, the success of these studies will inform the development Chk1 inhibitors in AML and other neoplastic diseases.