Metabolic Signature of Imatinib Resistance

伊马替尼耐药的代谢特征

• 批准号: 6925812
• 负责人: Natalie J. Serkova
• 金额: $ 13.24万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6925812
• 关键词: Krebs' cycle; antineoplastics; apoptosis; binding sites; bioassay; cell line; cell proliferation; chronic myelogenous leukemia; clinical research; cytogenetics; drug metabolism; drug resistance; drug screening /evaluation; gene expression; glucose metabolism; glucose transporter; glycolysis; human subject; metabolomics; method development; neoplasm /cancer chemotherapy; nuclear magnetic resonance spectroscopy; oncoproteins; phosphorylcholine

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.

描述（由申请人提供）：慢性髓性白血病（CML）可以说是研究最仔细和最了解的人类癌症。CML已经成为基础研究和临床研究的原型肿瘤，旨在开发治愈性癌症治疗。开发新的靶向癌症特异性疗法是肿瘤学的主要策略，而甲磺酸伊马替尼靶向抑制CML患者的Bcr-Abl酪氨酸激酶活性是第一个成功的概念证明。分子机制与伊马替尼疗效之间的相关性已得到很好的确立。然而，伊马替尼耐药的发展已成为一个重要的治疗问题，其中的病因似乎是多因素的，知之甚少。除了骨髓增生的反弹外，没有准确的临床标准来预测伊马替尼耐药性的发展。然而，有证据表明，葡萄糖-底物通量的控制是伊马替尼抗增殖作用的重要机制。这可以用来检测耐药性。此外，伊马替尼耐药胃肠道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患者细胞糖代谢变化和耐药发展的信息。磁共振波谱（MRS）已经迅速发展成为一种基于癌症代谢谱的癌症诊断和药物疗效评估的技术，应用越来越广泛。我们假设，人Bcr-Abl +细胞对伊马替尼治疗的代谢反应，可以通过MRS检测到，并预测特异性抑制细胞周期和诱导凋亡，将可靠地揭示对伊马替尼治疗的治疗敏感性。伊马替尼耐药的代谢特征，我们认为与葡萄糖和胆碱代谢有关，将通过多核磁共振成像在人CML细胞系和从伊马替尼治疗的CML患者分离的白细胞中进行评估。在未来，该研究的结果将有助于(i)开发临床基于核磁共振的外周血代谢谱（相当于实体肿瘤的PET研究），用于早期检测伊马替尼耐药性；（ii）评价新型小分子酪氨酸激酶抑制剂的代谢作用机制。