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.
Over 14,000 adults will be diagnosed with acute myeloid leukemia (AML) in the United Sates in 2014; and over 10,000 will die of the disease. This project will assess how Chk1 inhibition sensitizes AML cells to cytarabine, the standard therapy for this disease, and look for biomarkers that can predict responses to cytarabine plus Chk1 inhibitor in human AML samples from a clinical trial of the drug combination. The successful completion of these studies may improve therapy for AML patients.
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