Mayo Clinic Center for Clinical Proteomics

项目摘要/摘要 我们建议建立一个多学科的梅奥临床蛋白质组学临床中心，总体目标是 识别和验证多发性骨髓瘤治疗反应的蛋白质组生物标记物。这个中心是一个 独特的联盟由梅奥诊所的两支球队和杨百翰的一支球队组成 大学。梅奥诊所拥有多发性骨髓瘤专业知识的医生和科学家组成的团队 诊断、治疗、临床试验和基础研究以及质量等技术 将加入光谱学、基因组学、转录组学、生物信息学和临床分析开发 由杨百翰大学的一位新仪器/平台开发方面的世界专家创建 独特的中锋。多发性骨髓瘤是一种复杂的疾病，具有几种不同的细胞遗传学亚型。A最近 已开发的一类指定为免疫调节性亚胺类药物(IMiDS)已成为 多发性骨髓瘤的治疗，尽管患者的复发率很高，主要是因为耐药。这个 IMiDS的主要靶点是Cereblon(CRBN)，这是其抗癌和免疫活性所必需的。 IMID激活CRBN E3泛素连接酶复合体的酶活性，导致泛素化和 转录因子IKZF1和IKZF3的降解，从而调节肿瘤生存和免疫反应 通过下调IRF4和MYC。对于临床前手臂，我们的跨学科团队将承担 涉及全面蛋白质基因组学特征(蛋白质组、磷蛋白质组、 多发性骨髓瘤模型(人源化基因工程细胞系)的泛素组、基因组、转录组 小鼠模型和患者样本)，以确定IMiD抗性的分子标记。鉴于…的中心地位 CRBN介导的IMiD抗性途径，我们将通过以下方式启动我们的靶向蛋白质组学研究 重点开发针对CRBN及其下游效应物的靶向检测方法。同时，我们预计 通过我们的发现研究确定其他候选蛋白质，对其进行有针对性的分析也将是 发展起来的。最后，文森特·拉伊库马尔博士，这项提案的联合调查员，将提供从 由NCI赞助的三项临床试验，专门设计用于观察IMIDS的影响，使能够验证 候选人通过有针对性的方法。通过融合多种技术的不断发展 对于包括CyTOF在内的平台，我们将确保在提案期间保持敏捷性。 拥有成熟的先进基础设施，在CAP/CLIA分析开发方面经验丰富的人员， 专用仪器、高分析能力和现有的QC、数据处理和 生物信息学，拟议的梅奥临床蛋白质组学临床中心有望成功发现和 验证多发性骨髓瘤中IMiD耐药的蛋白质组学标志物。

PROJECT SUMMARY/ABSTRACT We propose to create a multidisciplinary Mayo Clinic Center for Clinical Proteomics with the overarching goal of identifying and validating proteomic biomarkers for treatment response in multiple myeloma. This center is a unique alliance comprising of two teams within the Mayo Clinic umbrella and one team at Brigham Young University. This team of physicians and scientists at Mayo Clinic with expertise in multiple myeloma diagnosis, treatment, clinical trials and basic research as well as technologies such as mass spectrometry, genomics, transcriptomics, bioinformatics and clinical assay development will be joined by a world expert in novel instrument/platform development at Brigham Young University to create a unique center. Multiple myeloma is a complex disease with several distinct cytogenetic subtypes. A recently developed class of drugs designated immunomodulatory imide drugs (IMiDs) has become a mainstay of treatment of multiple myeloma although relapses among patients is high mainly due to drug resistance. The primary target of IMiDs is cereblon (CRBN), which is absolutely required for its anti-cancer and immune activity. IMiDs activate the enzymatic activity of the CRBN E3 ubiquitin ligase complex leading to ubiquitylation and degradation of transcription factors IKZF1 and IKZF3, thereby regulating tumor survival and immune response through downregulation of IRF4 and MYC. For the preclinical arm, our interdisciplinary team will undertake discovery studies involving comprehensive proteogenomic characterization (proteome, phosphoproteome, ubiquitylome, genome, transcriptome) of multiple myeloma models (genetically engineered cell lines, humanized mouse models and patient samples) to identify molecular markers of IMiD resistance. Given the centrality of CRBN-mediated pathways in IMiD resistance, we will jumpstart our targeted proteomics efforts by focusing on developing targeted assays for CRBN and its downstream effectors. In parallel, we anticipate identifying additional candidate proteins through our discovery studies, for which targeted assays will also be developed. Finally, Dr. Vincent Rajkumar, a co-investigator on this proposal, will provide access to samples from three NCI-sponsored clinical trials specifically designed to look at effects of IMiDs enabling validation of candidates through a targeted approach. By incorporating continuous development of multiple technology platforms including CyTOF, we will ensure that we maintain agility over the duration of the proposal. With an established advanced infrastructure, personnel experienced in the development of CAP/CLIA assays, dedicated instrumentation, high analytical capacity and existing pipelines for QC, data handling and bioinformatics, the proposed Mayo Clinic Center for Clinical Proteomics is poised for success to discover and validate proteomic markers of IMiD resistance in multiple myeloma.