Integrating Diagnostics with Therapeutic Strategies in Chronic Myeloid Leukemia

慢性粒细胞白血病的诊断与治疗策略相结合

• 批准号: 8278463
• 负责人: Vivian G Oehler
• 金额: $ 35.42万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278463
• 关键词: BCR gene; Bioinformatics; Biological; Biological Assay; Biology; Blast Phase; CD34 gene; Candidate Disease Gene; Cell Line; Cells; Chronic Myeloid Leukemia; Chronic Phase; Chronic-Phase Myeloid Leukemia; Clinical; Clinical Research; Clinical Trials; Collaborations; Dasatinib; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Outcome; Disease Progression; Disease Resistance; Disease model; Dose; EZH2 gene; Early Diagnosis; Early identification; Enrollment; Erinaceidae; Event; FDA approved; Failure; Future; GLI2 gene; Gatekeeping; Gene Expression; Gene Silencing; Genes; Genomics; Gleevec; Goals; Health; Histone Deacetylase Inhibitor; Imatinib mesylate; Individual; Investigation; Kinetics; Lentivirus Vector; Link; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Modeling; Molecular; Molecular Cytogenetics; Molecular Profiling; Monitor; Mutation; Mutation Detection; Myelogenous; Newly Diagnosed; Outcome; Pathway interactions; Patient Care; Patients; Pattern; Phase; Play; Point Mutation; Protein Tyrosine Kinase; Publishing; Reaction; Recurrent disease; Relapse; Resistance; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Role; Sampling; Solid Neoplasm; Sorting - Cell Movement; Source; Southwest Oncology Group; Techniques; Testing; Therapeutic; Time; Treatment outcome; Tyrosine Kinase Inhibitor; Validation; YY1 Transcription Factor; advanced disease; base; bcr-abl Fusion Proteins; burden of illness; clinical application; design; effective therapy; high risk; improved; mRNA Expression; nanofluidic; neoplastic cell; novel; novel strategies; novel therapeutics; progenitor; prognostic; prospective; response; success; t(9; 22)(q34; q11); transcription factor; translational approach; translational study

DESCRIPTION (provided by applicant): Chronic myeloid leukemia (CML) provides a unique disease model in which to apply a translational approach to the study of the biology of disease progression, therapeutic response, and disease relapse. Although the function of BCR-ABL is well described, events involved in disease progression remain largely unknown. Over the last 10 years, tyrosine kinase inhibitors such as imatinib mesylate (IM) have dramatically altered CML treatment. Yet despite the excellent responses in most early chronic phase (CP) patients, ~20% of CP patients fail IM therapy. This number is higher for late CP patients and outcomes for advanced disease or disease resistant to IM are significantly poorer. Thus, a clear need exists for the early identification of patients at risk for disease progression or therapeutic resistance. The proposed translational studies rely on the identification of risk factors in patients, followed by validation in independent patients, with the ultimate goal of applying these finding to patient care in the clinical setting. The success of these investigations relies on the ability to test the findings in a sufficiently large number of patients. We are actively participating in a number of clinical trials for CML, including SWOG S0325, which compares standard dose IM to high dose IM and to dasatinib. In Specific Aim 1 diagnostic gene expression candidates associated with CML disease progression and therapy resistance that were previously identified in microarray studies will be validated using high throughput quantitative RT-PCR (QPCR) in 400 independent patient samples. Investigations will be expanded to identify microRNAs (miRNAs) associated with CML progression and therapy resistance using high throughput QPCR profiling for all currently known miRNAs. In Specific Aim 2 these diagnostic studies will be integrated with enhanced monitoring studies in patients receiving tyrosine kinase inhibitors (TKIs). These investigations will include early detection and monitoring of the kinetics of T315I development, a mutation resistant to all currently approved TKIs. Enhanced QPCR monitoring of bcr-abl in patients maintaining the best molecular responses will also be performed using a novel nanofluidic platform that enhances sensitivity through sample partitioning into up to 10,000 independent reactions. The goal of the T315I point mutation studies is to determine whether early T315I mutation detection can be used to guide therapeutic choices; the goal of enhanced bcr-abl monitoring in the best molecular response patients is to determine a kinetic profile that may potentially identify patients in whom TKI therapy can be stopped. Lastly, in Specific Aim 3 we will examine PRAME and GLI2 for their role in disease progression and therapy resistance in cell lines and primary cells using lentiviral vector-based gene silencing and expression techniques. A main goal will be to identify new pathways involved in progression and resistance that can be targeted either by existing therapies or by novel strategies. A major future clinical application of these integrated biological and clinical studies is to identify profiles that can be used to determine risk-based treatment management in individual patients. PUBLIC HEALTH RELEVANCE: Despite the success of therapy with imatinib mesylate (Gleevec, IM) in early chronic phase chronic myeloid leukemia (CML) patients, treatment outcomes for patients with more advanced disease or IM resistant disease remain poor. Our published and preliminary data allow us to investigate in clinical trial samples several important questions that may change how we manage CML: can we define diagnostic predictors of response; can we identify the pan-resistant T315I mutation early in the treatment course; can we determine a bcr-abl mRNA pattern in the best responders that may identify a group of patients who may be able to stop therapy; and through a better understanding of the biology of CML progression can we identify targets for therapy and reasons for resistance? These findings will be used to create risk-based profiles that will ultimately be used in the clinical setting in individual patients to tailor therapy.

描述（由申请人提供）：慢性粒细胞白血病（CML）提供了一种独特的疾病模型，在该模型中应用转化方法来研究疾病进展、治疗反应和疾病复发的生物学。尽管 BCR-ABL 的功能已得到很好的描述，但与疾病进展相关的事件仍然很大程度上未知。在过去 10 年中，酪氨酸激酶抑制剂（例如甲磺酸伊马替尼 (IM)）极大地改变了 CML 的治疗。然而，尽管大多数早期慢性期 (CP) 患者的反应良好，但约 20% 的 CP 患者未能接受 IM 治疗。晚期 CP 患者的这一数字更高，而晚期疾病或 IM 耐药疾病的结果则明显较差。因此，明确需要早期识别处于疾病进展或治疗耐药风险的患者。拟议的转化研究依赖于识别患者的危险因素，然后在独立患者中进行验证，最终目标是将这些发现应用于临床环境中的患者护理。这些研究的成功依赖于在足够多的患者中测试结果的能力。我们正在积极参与多项针对 CML 的临床试验，包括 SWOG S0325，该试验将标准剂量 IM 与高剂量 IM 以及达沙替尼进行比较。在特定目标 1 中，将使用高通量定量 RT-PCR (QPCR) 在 400 个独立患者样本中验证先前在微阵列研究中确定的与 CML 疾病进展和治疗耐药性相关的诊断基因表达候选者。将扩大研究范围，通过对所有目前已知的 miRNA 进行高通量 QPCR 分析来识别与 CML 进展和治疗耐药相关的 microRNA (miRNA)。在具体目标 2 中，这些诊断研究将与接受酪氨酸激酶抑制剂 (TKI) 的患者的强化监测研究相结合。这些研究将包括早期检测和监测 T315I 发育动力学，T315I 是一种对所有目前批准的 TKI 具有抗性的突变。还将使用新型纳米流体平台对维持最佳分子反应的患者中的 bcr-abl 进行增强 QPCR 监测，该平台通过将样品分配为多达 10,000 个独立反应来增强灵敏度。 T315I点突变研究的目标是确定早期T315I突变检测是否可用于指导治疗选择；在最佳分子反应患者中加强 bcr-abl 监测的目标是确定可能识别可以停止 TKI 治疗的患者的动力学特征。最后，在具体目标 3 中，我们将使用基于慢病毒载体的基因沉默和表达技术检查 PRAME 和 GLI2 在细胞系和原代细胞的疾病进展和治疗耐药中的作用。主要目标是确定涉及进展和耐药的新途径，可以通过现有疗法或新策略来针对这些途径。这些综合生物学和临床研究未来的一个主要临床应用是确定可用于确定个体患者基于风险的治疗管理的概况。公共卫生相关性：尽管甲磺酸伊马替尼（格列卫，IM）治疗早期慢性期慢性粒细胞白血病（CML）患者取得了成功，但对于晚期疾病或 IM 耐药性疾病患者的治疗结果仍然较差。我们已发表的初步数据使我们能够在临床试验样本中研究几个可能改变我们管理 CML 方式的重要问题：我们能否定义反应的诊断预测因子？我们能否在治疗过程的早期识别出泛耐药T315I突变？我们能否确定最佳反应者的 bcr-abl mRNA 模式，从而确定一组能够停止治疗的患者？通过更好地了解 CML 进展的生物学，我们能否确定治疗目标和耐药原因？这些发现将用于创建基于风险的概况，最终将用于个体患者的临床环境以定制治疗。