Metabolic Signature of Imatinib Resistance

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DESCRIPTION (provided by applicant): Chronic myelogenous leukemia (CML) is arguably the most carefully studied and best understood cancer in humans. CML has served as a prototype neoplasm for basic research as well as for clinical studies designed to develop curative cancer treatment. Development of novel targeted cancer-specific therapies is a major strategy in oncology, whereas, targeted inhibition of Bcr-Abl tyrosine kinase activity by imatinib mesylate in CML patients was the first successful proof of concept. The correlation between the molecular mechanisms and imatinib efficacy is well established. However, the development of imatinib resistance has become a significant therapeutic problem, in which the etiology appears to be multifactoral and poorly understood. There are no precise clinical criteria to predict the development of imatinib resistance, other than rebound of the myeloproliferation. However, there is evidence that the control of glucose-substrate flux is an important mechanism of the antiproliferative action of imatinib. that could be utilized to detect resistance. Moreover, imatinib-resistant gastrointestinal c-Kit tumors reveal highly elevated glucose uptake in clinical positron emission tomography (PET) scans. Unlike solid-tumor patients, CML patients do not undergo assessment by PET. Currently, there is no information about the changes in cell glucose metabolism under imatinib treatment and resistance development in CML patients. Magnetic resonance spectroscopy (MRS) has rapidly evolved to be a technique with increasingly broad applications in cancer diagnosis and drug efficacy evaluations based on cancer metabolic profiling. We hypothesize that the metabolic response to imatinib treatment in human Bcr-Abl + cells, which is detectable by MRS and predictive to specific inhibition of cell cycle and induction of apoptosis, will reliably reveal the therapeutic sensitivity to imatinib treatment. The metabolic signature of imatinib resistance, which we believe to be related to glucose and choline metabolism, will be evaluated by multinuclear MRS in human CML cell lines and in leukocytes isolated from imatinib treated CML patients. In the future, the results of the study will help (i) to develop a clinical MRS-based metabolic profile in peripheral blood (equivalent to PET studies in solid tumors) for the early detection of imatinib resistance; and (ii) to evaluate the metabolic mechanisms of action for novel small molecule tyrosine kinase inhibitors.