Clonal Evolution in Multiple Myeloma

多发性骨髓瘤的克隆进化

基本信息

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
项目类别：
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

项目摘要

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).

抽象的该应用的主要目的是进行预示介绍所需的翻译工作多发性骨髓瘤（MM）中的下一代测序临床诊断。为基于这个目标的基础，我们设计和试行了创新的，特定于77基因面板（M3P）。面板需要最小的DNA 数量，同时跟踪副本号和存在常见的放大和缺失。使用这种新颖的资源并利用梅奥（Mayo）的大量临床注释，组织库和患者人群，我们将首次成为有可能解决患病率，预后含义以及对每一个的热反应的影响在大量患者的MM细胞中鉴定出的常见突变，成本相对较低。在AIM 1中，我们将询问77个最常见的突变或耐药性基因中的每一个单独或通过726个肿瘤DNA中的途径或不监督的簇组装时诊断患者。这项工作将定义该人群中突变的频谱和频率。将单个突变的存在与基线临床和实验室特征相关联，反应治疗及其对继电器和生存的贡献。在AIM 2中，我们将在治疗之前，期间和之后跟踪疾病的克隆进化最小生存疾病和早期的“前体”细胞室。具体来说，我们将进行所有梅奥场地的前瞻性，第2阶段临床试验，分配给124名复发患者单独使用五层胺和地塞米松治疗或与Carfilzomib结合使用相同的药物。 M3P测序将用于表征存活的突变曲线和克隆多样性肿瘤克隆在不同的骨髓室和外周血中；在第2周期结束时治疗， 6个月。最后，在AIM 3中，我们将在一般情况下生成无偏的序列数据，以及特别是CRBN/IZKF1/IKZF3/IRF4，IRE1/XBP1或NR3C1突变的频率，有助于药物高度耐药患者的抗性。为了涵盖已知的，但也寻求新的突变，我们将使用整个外显子组和RNA测序首次检查真正药物难治的分子谱 60例死亡后6个月内或入学时，有60例骨髓样品的毫米在任何I期试验中（包括此孢子应用中的试验）。