Clonal Evolution in Multiple Myeloma

多发性骨髓瘤的克隆进化

• 批准号: 8930236
• 负责人: ALEXANDER KEITH STEWART
• 金额: $ 26.15万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8930236
• 关键词: Address; Affect; Biology; Cell Count; Cells; Cessation of life; Characteristics; Clinic; Clinical; Clinical Management; Clinical Trials; Clonal Evolution; DNA; Data; Development; Dexamethasone; Diagnosis; Diagnostic; Disease; Drug resistance; Enrollment; Frequencies; Genes; Genetic; Genetic Heterogeneity; Genome; Genomics; Goals; IRF4 gene; Individual; Knowledge; Laboratories; Light; Marrow; Mind; Molecular Profiling; Monitor; Multiple Myeloma; Mutate; Mutation; NR3C1 gene; Newly Diagnosed; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Population; Prevalence; RNA Sequences; Recurrence; Refractory; Relapse; Reporting; Residual Tumors; Resources; Role; Sampling; Series; Site; Staging; Technology; Therapeutic; Time; Tissue Banking; Tissue Banks; Translating; Vision; Work; base; chemotherapy; clinical practice; clinically actionable; cohort; cost; design; exome sequencing; gene panel; genome sequencing; innovation; next generation sequencing; novel; outcome forecast; patient population; peripheral blood; phase I trial; precursor cell; prognostic; prospective; response; transcriptome sequencing; tumor; tumor DNA

ABSTRACT A major goal of this application is to conduct the translational work required to foreshadow the introduction of a next generation sequencing clinical diagnostic in Multiple Myeloma (MM). Underpinning this goal, we designed and piloted an innovative, MM specific, 77-gene panel (M3P). The panel requires minimal DNA quantities, generating sequence at significant depth while simultaneously tracking copy number and presence of common amplifications and deletions. Using this novel resource and capitalizing on the extensive clinically annotated, tissue banks and patient populations at Mayo, we will, for the first time be able to address the prevalence, prognostic implications, and effect on therapeutic responses of each of the common mutations identified in MM cells in large series of patients at relatively low cost. In Aim 1 we will interrogate each of the 77 most commonly mutated, or drug resistance related genes, individually or when assembled by pathways or non-supervised clusters in tumor DNA from 726 newly diagnosed patients. This work will define the spectrum and frequency of mutations in this population; correlate the presence of individual mutations to baseline clinical and laboratory characteristics, response to therapy, and their contribution to relapse and survival. In Aim 2 we will track clonal evolution of disease before, during and after therapy including in states of minimal surviving disease and in earlier “precursor” cell compartments. Specifically, we will conduct a prospective, phase 2 clinical trial across all Mayo sites enrolling 124 relapsing patients assigned to treatment with pomalidomide and dexamethasone alone or the same drugs in combination with carfilzomib. M3P sequencing will be used to characterize the mutational profile and clonal diversity of the surviving tumor clone in different marrow compartments and in peripheral blood; pre therapy, at end of cycle 2, and at 6 months. Finally, in Aim 3 we will generate unbiased sequence data on the mutational profile in general, and the frequency of CRBN/IZKF1/IKZF3/IRF4, IRE1/XBP1s or NR3C1 mutations in particular, contributing to drug resistance in highly drug resistant patients. To cover known, but also seek new mutations, we will use whole exome and RNA sequencing to examine for the first time the molecular profile of truly drug refractory MM in 60 patients with a marrow sample taken within 6 months of death from MM or at time of enrollment on any Phase I trial (including trials in this SPORE application).

摘要 此应用程序的一个主要目标是执行所需的翻译工作，以便为介绍做好准备 多发性骨髓瘤(MM)的下一代测序临床诊断。为了支持这一目标，我们 设计并试验了一种创新的MM特定的77基因小组(M3P)。该面板只需要最低限度的DNA 数量，在显著深度生成序列，同时跟踪拷贝数和 存在常见的扩增和缺失。利用这一新颖的资源，并利用 广泛的临床注释，组织库和患者群体在梅奥，我们将第一次 能够解决每一种疾病的发病率、预后影响和对治疗反应的影响 在大量患者的多发性骨髓瘤细胞中发现了常见的突变，成本相对较低。 在目标1中，我们将询问77个最常见的突变或耐药相关基因， 来自726个新的肿瘤DNA中的单独或通过通路或非监督簇组装时 确诊的病人。这项工作将定义这一群体中突变的频谱和频率； 将个体突变的存在与基线临床和实验室特征、反应 治疗，以及他们对复发和生存的贡献。 在目标2中，我们将跟踪疾病在治疗前、治疗中和治疗后的克隆进化，包括在 存活量最小的疾病和早期的“前体”细胞隔间。具体来说，我们将进行一项 在所有Mayo站点进行的前瞻性2期临床试验，招募了124名复发患者，分配到 泊马度胺和地塞米松单独或与卡菲佐米联合治疗。 M3P测序将被用来表征存活的突变图谱和克隆多样性 不同骨髓室和外周血中的肿瘤克隆；治疗前、周期2结束时和 6个月的时候。 最后，在目标3中，我们将生成关于突变图谱的一般无偏序列数据，并且 尤其是CRBN/IZKF1/IKZF3/IRF4、IRE1/XBP1s或NR3C1突变的频率，与药物有关 高度耐药患者的耐药性。为了覆盖已知的，但也寻求新的突变，我们将使用 全外显子组和RNA测序首次检测真正药物难治性的分子图谱 60例多发性骨髓瘤患者在死亡后6个月内或登记时采集骨髓样本 在任何I期试验中(包括本孢子应用中的试验)。