Targeting Chk1 in Acute Myeloid Leukemia

靶向 Chk1 治疗急性髓系白血病

• 批准号: 9115542
• 负责人: LARRY M KARNITZ
• 金额: $ 36.37万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-24 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9115542
• 关键词: Acute Myelocytic Leukemia; Adult; Adult Acute Myeloblastic Leukemia; Affect; Anthracyclines; Antineoplastic Agents; Biological Markers; Biopsy Specimen; Cell Death; Cells; Clinical Trials; Cytarabine; DNA; DNA replication fork; DNA replication origin; Data; Development; Diagnosis; Disease; Disease Resistance; Disease remission; Drug Combinations; Drug resistance; Effectiveness; Enzymes; Event; Generations; Goals; Hand; Health; Human; Lead; Long-Term Survivors; Marrow; Mediating; Molecular; Mutate; Mutation; NPM1 gene; Neoplasms; Participant; Pathway interactions; Patients; Pharmacologic Substance; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phosphorylation; Play; Process; Proteins; Refractory; Regulation; Relapse; Role; Sampling; Signal Pathway; Signal Transduction; Stress; Toxic effect; Treatment Protocols; base; chemotherapy; cytotoxicity; improved; inhibitor/antagonist; leukemia; mutant; neoplastic; novel marker; potential biomarker; preclinical study; predicting response; prevent; response; small molecule; small molecule inhibitor; stem; success; therapy development; trial comparing

 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.

 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系白血病 (AML)。标准疗法是阿糖胞苷 (AraC) 加蒽环类药物的组合。尽管这种治疗方案缓解率很高，但大约 30% 的成人 AML 对主要化疗耐药，超过 50% 的患者会复发并对其他治疗耐药。因此，迫切需要开发更好的疗法来治疗 AML 或预防耐药性疾病的发展。 解决这个问题的一种方法是通过小分子抑制剂靶向 Chk1（ATR-Chk1 信号通路的核心参与者）来增强 AraC 的活性。这种方法源于 1) 对 ATR-Chk1 信号通路的广泛机制和临床前研究表明，该通路可保护白血病细胞免受 AraC 诱导的细胞毒性，以及 2) 小分子 Chk1 抑制剂的开发，这些抑制剂目前正在进行临床试验，在肿瘤疾病中显示出令人兴奋的活性，且不会增加毒性，包括最近完成的 AraC 加 Chk1 的 1 期试验 抑制剂。 尽管取得了这些进展，但 Chk1 的分子功能以及 Chk1 抑制在 AML 中的机制后果仍然知之甚少。此外，目前还不清楚为什么有些患者对这种疗法有反应而另一些患者则没有。我们的中心假设是，通过了解 AraC 处理的 AML 细胞中 Chk1 的功能和调节，我们可以识别与 Chk1 抑制剂反应相关的生物标志物，从而为有效开发和部署 Chk1 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 Chk1 如何调节经 AraC 治疗的 AML 细胞的存活，并确定 Chk1 抑制如何导致细胞死亡，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，帮助选择最有可能对 Chk1 抑制剂治疗产生反应的患者。有了这些信息，我们将准备探索这些潜力是否 在一项正在进行的 2 期试验中，生物标志物与 AraC+Chk1 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 Chk1 抑制剂疗法开发的独特机会，因为 2 期试验是第一个在 Chk1 抑制可能有益的疾病环境中使用高选择性 Chk1 抑制剂的试验。重要的是，这些研究的成功将为 AML 和其他肿瘤疾病的 Chk1 抑制剂的开发提供信息。