Examination of imatinib mesylate resistance in CML

CML 甲磺酸伊马替尼耐药性检查

• 批准号: 7097434
• 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/7097434
• 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博士在5年的时间内的目标是预期评估慢性阶段（CP）CML患者中对伊马替尼甲酸酯抗性的机制，并研究至少获得MCR的患者的复发生物学。根据虹膜研究结果，伊马替尼已成为第一线治疗。但是，响应的耐用性尚不清楚，同种异体移植仍然是唯一的潜在治愈方法。鉴于CML治疗策略的快速变化，明确需要在治疗早期（理想情况下治疗）中识别反应的预测指标。 具体目的1。评估分子反应和对伊马替尼反应的临床预测指标。通过RT-PCR评估的BCR-ABL消失的动力学预测了对同种异体移植和干扰素治疗的复发和反应。 Hasford评分已用于评估干扰素或化学疗法治疗的患者的预后。分配给SWOG S0325四臂的所有患者将通过RTPCR评估。 我们假设在开始治疗后三到六个月内，BCR-ABL的动力学降低将与反应持续时间相关，并且Hasford得分预测了对伊马替尼的早期反应。 特定目的2。通过基因组表达分析确定反应和复发的遗传预测因子。微阵列技术已用于开发基因组谱，比病理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患者中鉴定出反应的预处理基因组预测指标。这些预测因素将在SWOG S0325上进行前瞻性验证。我们假设伊马替尼的反应者的表达谱将与非反应者不同，并且低风险和高风险Hasford得分将具有与结果相关的不同基因表达谱。 特定目的3。确定通过点突变分析和基因组表达分析的复发生物学。已经描述了几种对伊马替尼抗性的机制。点突变的患病率将由PCR-SSCP和敏感的错配测定法评估，以确定治疗前和早期点突变的频率。 我们假设突变频率很高，可以在治疗前检测到。 复发样品的基因表达模式将与相应的诊断样品进行比较。 我们假设先前未发现的克隆的演变是复发的机制。