Metabolic Signature of Imatinib Resistance

描述（由申请人提供）：慢性粒细胞白血病（CML）可以说是人类中研究最仔细和最了解的癌症。慢性粒细胞白血病已作为原型肿瘤的基础研究以及临床研究，旨在开发治愈性癌症治疗。开发新型靶向癌症特异性治疗是肿瘤学的主要策略，而在CML患者中通过甲磺酸伊马替尼靶向抑制Bcr-Abl酪氨酸激酶活性是第一个成功的概念证明。分子机制和伊马替尼疗效之间的相关性已得到充分确立。然而，伊马替尼耐药的发展已成为一个重要的治疗问题，其中病因似乎是多因素的，知之甚少。除了骨髓增殖的反弹之外，没有精确的临床标准来预测伊马替尼耐药的发展。然而，有证据表明，葡萄糖底物流量的控制是伊马替尼的抗增殖作用的重要机制。可以用来检测耐药性。此外，伊马替尼耐药的胃肠道c-Kit肿瘤在临床正电子发射断层扫描（PET）中显示葡萄糖摄取高度升高。与实体瘤患者不同，CML患者不接受PET评估。目前，还没有关于伊马替尼治疗下CML患者细胞葡萄糖代谢变化和耐药发展的信息。磁共振波谱（MRS）已迅速发展成为一种技术，在癌症诊断和基于癌症代谢谱的药物疗效评价中具有越来越广泛的应用。我们假设，代谢反应伊马替尼治疗的人Bcr-Abl +细胞，这是可检测的MRS和预测特异性抑制细胞周期和诱导细胞凋亡，将可靠地揭示伊马替尼治疗的敏感性。我们认为伊马替尼耐药的代谢特征与葡萄糖和胆碱代谢相关，将通过人CML细胞系和从伊马替尼治疗的CML患者分离的白细胞中的多核MRS进行评价。在未来，该研究的结果将有助于（i）在外周血中开发基于MRS的临床代谢谱（相当于实体瘤中的PET研究），用于早期检测伊马替尼耐药性;（ii）评估新型小分子酪氨酸激酶抑制剂的代谢作用机制。

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.