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）：可以说是人类中最仔细研究，最熟悉的癌症的慢性骨髓性白血病（CML）。 CML曾是基础研究的原型肿瘤，以及旨在开发治疗癌症治疗的临床研究。新型靶向癌症特异性疗法的开发是肿瘤学的主要策略，而在CML患者中，伊马替尼甲酸酯靶向抑制BCR-Abl酪氨酸激酶活性是第一个成功的概念证明。分子机制与伊马替尼疗效之间的相关性已很好。然而，伊马替尼抗性的发展已成为一个重大的治疗问题，其中病因似乎是多因素且知名度不佳的。除了骨髓增生的反弹之外，没有精确的临床标准可以预测伊马替尼抵抗的发展。然而，有证据表明，控制葡萄糖 - 基底通量是伊马替尼抗增殖作用的重要机制。可以用来检测电阻。此外，抗伊马替尼耐药的胃肠道C-KIT肿瘤显示临床正电子发射断层扫描（PET）扫描中葡萄糖的摄取高度升高。与固体肿瘤患者不同，CML患者不会通过PET进行评估。当前，在伊马替尼治疗和CML患者的耐药性发展下尚无有关细胞葡萄糖代谢的变化的信息。磁共振光谱（MRS）已迅速发展为一种基于癌症代谢分析的癌症诊断和药物疗效评估中越来越广泛应用的技术。我们假设人类BCR-ABL +细胞中对伊马替尼治疗的代谢反应，可通过MRS检测到，并且可以预测细胞周期的特定抑制和凋亡的诱导，将可靠地揭示出对伊马替尼治疗的治疗敏感性。伊马替尼抵抗的代谢特征，我们认为与葡萄糖和胆碱代谢有关，将通过人类CML细胞系中的多核MRS以及从伊马替尼治疗的CML患者分离的白细胞中评估。将来，该研究的结果将有助于（i）在周围血液（相当于实体瘤研究）中开发基于临床MRS的代谢特征，以早日检测到伊马替尼抗性； （ii）评估新型小分子酪氨酸激酶抑制剂的作用代谢机制。