Metabolic Signature of Imatinib Resistance

伊马替尼耐药的代谢特征

基本信息

批准号：
7037675
负责人：
Natalie J. Serkova
金额：
$ 12.93万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2008-03-31
项目状态：
已结题

项目摘要

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）：慢性粒细胞白血病（CML）可以说是人类研究最仔细、理解最透彻的癌症。 CML 已成为基础研究以及旨在开发治愈性癌症治疗的临床研究的原型肿瘤。开发新型靶向癌症特异性疗法是肿瘤学的主要策略，而甲磺酸伊马替尼在 CML 患者中靶向抑制 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明确。然而，伊马替尼耐药性的发展已成为一个重要的治疗问题，其病因似乎是多因素的且知之甚少。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，控制葡萄糖底物通量是伊马替尼抗增殖作用的重要机制。可以用来检测阻力。此外，临床正电子发射断层扫描 (PET) 扫描显示，伊马替尼耐药的胃肠道 c-Kit 肿瘤的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。目前尚无关于伊马替尼治疗下细胞糖代谢变化以及CML患者耐药发生的信息。磁共振波谱（MRS）已迅速发展成为一种在癌症诊断和基于癌症代谢谱的药物疗效评估中应用日益广泛的技术。我们假设人类 Bcr-Abl + 细胞对伊马替尼治疗的代谢反应（可通过 MRS 检测）并预测细胞周期的特异性抑制和细胞凋亡的诱导，将可靠地揭示对伊马替尼治疗的治疗敏感性。我们认为伊马替尼耐药的代谢特征与葡萄糖和胆碱代谢有关，将通过人类 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 进行评估。未来，该研究结果将有助于（i）开发基于临床MRS的外周血代谢谱（相当于实体瘤中的PET研究），以早期检测伊马替尼耐药； (ii) 评估新型小分子酪氨酸激酶抑制剂的代谢作用机制。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Time-dependent effects of imatinib in human leukaemia cells: a kinetic NMR-profiling study.

DOI：
10.1038/sj.bjc.6604946
发表时间：
2009-03-24
期刊：
BRITISH JOURNAL OF CANCER
影响因子：
8.8
作者：
Klawitter, J.;Anderson, N.;Klawitter, J.;Christians, U.;Leibfritz, D.;Eckhardt, S. G.;Serkova, N. J.
通讯作者：
Serkova, N. J.

Use of nuclear magnetic resonance-based metabolomics in detecting drug resistance in cancer.