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）：慢性髓样白血病（CML）提供了一种独特的疾病模型，其中将转化方法应用于疾病进展，治疗反应和疾病复发的生物学研究。尽管很好地描述了BCR-ABL的功能，但与疾病进展有关的事件在很大程度上尚不清楚。在过去的10年中，酪氨酸激酶抑制剂（例如伊马替尼）（IM）急剧改变了CML处理。尽管大多数早期慢性期（CP）患者的反应良好，但约有20％的CP患者失败了IM治疗。晚期CP患者的这个数字较高，而晚期疾病或抗病性IM的结果明显较差。因此，明确的需求是早期鉴定出患有疾病进展或治疗性抗性风险的患者。拟议的翻译研究依赖于患者中风险因素的识别，然后在独立患者中进行验证，其最终目的是将这些发现应用于临床环境中的患者护理。这些研究的成功取决于能够测试足够多的患者中发现结果的能力。我们正在积极参加许多CML的临床试验，包括SWOG S0325，将标准剂量IM与高剂量IM和Dasatinib进行了比较。在特定的目标1中，先前在微阵列研究中鉴定出的与CML疾病进展和耐药性相关的诊断基因表达候选者将在400个独立的患者样本中使用高通量定量RT-PCR（QPCR）进行验证。将扩大研究，以鉴定与CML进展和耐药性相关的microRNA（miRNA），并使用所有当前已知的miRNA的高吞吐量QPCR分析。在特定的目标2中，这些诊断研究将与接受酪氨酸激酶抑制剂（TKIS）的患者的监测研究相结合。这些研究将包括对T315I开发动力学的早期检测和监测，这是对当前批准的TKI的所有抗突变。在维持最佳分子反应的患者中，BCR-ABL的QPCR监测增强了，还将使用新型的纳米流体平台进行，该平台通过样本分配到多达10,000个独立反应来增强灵敏度。 T315i点突变研究的目的是确定早期T315i突变检测是否可以用于指导治疗选择。在最佳分子反应患者中增强BCR-ABL监测的目的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，在特定目标3中，我们将使用基于慢病毒载体的基因沉默和表达技术来研究它们在细胞系和原代细胞中疾病进展和抗病耐药性中的作用。一个主要目标是确定与现有疗法或新型策略有关的涉及进展和抵抗的新途径。这些综合生物学和临床研究的主要未来临床应用是确定可用于确定个别患者基于风险的治疗管理的特征。公共卫生相关性：尽管在早期慢性慢性骨髓性白血病（CML）患者中，乳接受甲酸酯（Gleevec，im）的治疗成功，但患有更晚期疾病或IM耐药性疾病的患者的治疗结果仍然很差。我们发表的和初步的数据使我们能够在临床试验样本中调查一些可能改变我们管理CML的重要问题：我们可以定义反应的诊断预测指标；我们可以在治疗过程的早期确定耐泛力的T315i突变吗？我们可以在最佳反应者中确定BCR-ABL mRNA模式，这些模式可能会识别一组可能能够停止治疗的患者；通过更好地了解CML进展的生物学，我们可以确定靶标的治疗和抗药性原因吗？这些发现将用于创建基于风险的概况，最终将在个别患者的临床环境中用于量身定制治疗。