Targeting Chk1 in Acute Myeloid Leukemia

 描述(申请人提供)：2014年，美国将有超过14,000名成年人被诊断为急性髓系白血病(AML)。标准疗法是阿糖胞苷(AraC)和一种蒽环类药物的组合。虽然这种治疗方案的缓解率很高，但大约30%的成人AML对初次化疗无效，超过50%的患者会复发并对其他治疗无效。因此，迫切需要开发更好的疗法来治疗AML或防止耐药疾病的发展。解决这一问题的一种方法是通过用小分子抑制剂靶向ATR-Chk1信号通路的中心参与者Chk1来增强AraC的活性。这一方法源于1)对ATR-Chk1信号通路的广泛机制和临床前研究，表明该途径可以保护白血病细胞免受AraC诱导的细胞毒性；2)小分子Chk1抑制剂的开发目前正在进行临床试验，并且在肿瘤疾病中显示出令人兴奋的活性，而毒性没有增加，包括最近完成的AraC加Chk1抑制剂的1期试验。尽管取得了这些进展，但Chk1的分子功能以及抑制Chk1在AML中的机制后果仍然知之甚少。此外，目前还不清楚为什么一些患者对这种疗法有反应，而另一些患者没有。我们的中心假设是，通过了解在AraC处理的AML细胞中Chk1的功能和调节，我们可以识别与Chk1抑制剂的反应相关的生物标记物，从而为有效地开发和部署Chk1抑制剂治疗AML和其他肿瘤铺平道路。这项建议的主要目标是确定Chk1如何调节经AraC治疗的AML细胞的生存，并确定Chk1抑制如何促进细胞死亡，作为一种手段，1)机械地评估Chk1功能，2)识别潜在的生物标志物，将帮助选择最有可能对Chk1抑制剂治疗有反应的患者。有了这些信息，我们将准备探索这些潜在的 在一项正在进行的第二阶段试验中，生物标志物与AraC+Chk1抑制剂的抗白血病反应有关。值得注意的是，这些研究代表着Chk1抑制剂疗法发展的一个独特机会，因为第二阶段试验是第一次使用高度选择性的Chk1抑制剂I，在这种疾病背景下，抑制Chk1可能是有益的。重要的是，这些研究的成功将为Chk1抑制剂在急性髓细胞白血病和其他肿瘤疾病中的开发提供信息。

 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.