Examination of imatinib mesylate resistance in CML

CML 甲磺酸伊马替尼耐药性检查

• 批准号: 6762099
• 负责人: Vivian G Oehler
• 金额: $ 13.37万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-09 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6762099
• 关键词: antineoplastics; biomarker; cancer risk; chronic disease /disorder; chronic myelogenous leukemia; clinical research; drug resistance; gene expression; gene expression profiling; genetic polymorphism; human genetic material tag; human subject; microarray technology; neoplasm /cancer chemotherapy; neoplasm /cancer genetics; neoplasm /cancer pharmacology; patient care management; patient oriented research; prognosis; pyrimidine analog; relapse /recurrence

DESCRIPTION (provided by applicant): Dr. Oehler's objective over 5 years is to prospectively assess mechanisms of resistance to imatinib mesylate in chronic phase (CP) CML patients and investigate the biology of relapse in patients who have obtained at least a MCR. Imatinib has become first line therapy based on the IRIS study results. However, the durability of response is unknown, and allogeneic transplant remains the only potential cure. Given the rapid change in treatment strategy for CML there is a clear need to identify predictors of response early in therapy, ideally pre-treatment. Specific Aim 1. Assess molecular response and clinical predictors of response to imatinib. The kinetics of bcr-abl disappearance as assessed by RT-PCR predict relapse and response to allogeneic transplant and interferon therapy. The Hasford score has been utilized to assess prognosis in patients treated with interferon or chemotherapy. All patients assigned to the four arms of SWOG S0325 will be assessed by RTPCR. We hypothesize that the kinetics of bcr-abl decrease within three to six months of initiating treatment will correlate with duration of response, and that the Hasford score predicts early response to imatinib. Specific Aim 2. Determine the genetic predictors of response and relapse by genomic expression analysis. Microarray technology has been used to develop genomic profiles that may be more predictive of prognosis than pathology or cytogenetics. Pre-treatment genomic predictors of response will be identified in chronic phase CML patients by microarray analysis. These predictors will be validated prospectively on SWOG S0325. We hypothesize that imatinib responders will have different expression profiles than non-responders and that low, intermediate, and high risk Hasford scores will have distinct gene expression profiles that correlate with outcome. Specific Aim 3. Determine the biology of relapse by point mutation analysis and genomic expression analysis. Several mechanisms of resistance to imatinib have been described. The prevalence of point mutations will be assessed by PCR-SSCP and by a sensitive mismatch assay to determine the frequency of point mutations pre- and early in treatment. We hypothesize that mutations frequency is high and is detectable before treatment. The gene expression pattern of the relapsed sample will be compared with the corresponding diagnostic sample. We hypothesize that the evolution of a previously undetected clone is the mechanism of relapse.

描述（由申请人提供）：Oehler 博士 5 年来的目标是前瞻性评估慢性期 (CP) CML 患者对甲磺酸伊马替尼的耐药机制，并研究至少获得 MCR 的患者复发的生物学。根据 IRIS 研究结果，伊马替尼已成为一线治疗药物。然而，反应的持久性尚不清楚，同种异体移植仍然是唯一可能的治疗方法。鉴于 CML 治疗策略的快速变化，显然需要在治疗早期（最好是在治疗前）确定反应的预测因子。 具体目标 1. 评估伊马替尼反应的分子反应和临床预测因子。 RT-PCR 评估的 bcr-abl 消失动力学可预测复发以及对同种异体移植和干扰素治疗的反应。 Hasford 评分已用于评估接受干扰素或化疗的患者的预后。分配到 SWOG S0325 四个组的所有患者都将通过 RTPCR 进行评估。 我们假设 bcr-abl 的动力学在开始治疗后三到六个月内下降将与反应持续时间相关，并且 Hasford 评分预测伊马替尼的早期反应。 具体目标 2. 通过基因组表达分析确定缓解和复发的遗传预测因子。微阵列技术已用于开发基因组图谱，该图谱可能比病理学或细胞遗传学更能预测预后。通过微阵列分析，将在慢性期 CML 患者中确定治疗前反应的基因组预测因子。这些预测变量将在 SWOG S0325 上进行前瞻性验证。我们假设伊马替尼应答者将具有与无应答者不同的表达谱，并且低、中和高风险 Hasford 评分将具有与结果相关的不同基因表达谱。 具体目标 3. 通过点突变分析和基因组表达分析确定复发的生物学。已经描述了伊马替尼的几种耐药机制。将通过 PCR-SSCP 和敏感错配测定来评估点突变的发生率，以确定治疗前和治疗早期点突变的频率。 我们假设突变频率很高并且在治疗前即可检测到。 复发样本的基因表达模式将与相应的诊断样本进行比较。 我们假设先前未检测到的克隆的进化是复发的机制。