Mayo Clinic Center for Clinical Proteomics

项目概要/摘要 我们建议建立一个多学科梅奥诊所临床蛋白质组学中心，其总体目标是 识别和验证多发性骨髓瘤治疗反应的蛋白质组生物标志物。这个中心是一个 由梅奥诊所旗下的两支团队和杨百翰的一支团队组成的独特联盟 大学。梅奥诊所的这支医生和科学家团队拥有多发性骨髓瘤方面的专业知识 诊断、治疗、临床试验和基础研究以及大规模检测等技术 将加入光谱分析、基因组学、转录组学、生物信息学和临床检测开发 由杨百翰大学的一位世界级新型仪器/平台开发专家创建 独特的中心。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。最近一个 已开发的一类指定免疫调节酰亚胺药物（IMiD）的药物已成为免疫调节药物的中流砥柱 多发性骨髓瘤的治疗虽然患者复发率很高，但主要是由于耐药性。的 IMiD 的主要目标是 cereblon (CRBN)，这是其抗癌和免疫活性所必需的。 IMiD 激活 CRBN E3 泛素连接酶复合物的酶活性，导致泛素化和 降解转录因子 IKZF1 和 IKZF3，从而调节肿瘤存活和免疫反应 通过下调 IRF4 和 MYC。对于临床前臂，我们的跨学科团队将承担 涉及全面蛋白质组表征（蛋白质组、磷酸蛋白质组、 多发性骨髓瘤模型（基因工程细胞系、人源化细胞系、泛素组、基因组、转录组） 小鼠模型和患者样本）来识别 IMiD 耐药性的分子标记。鉴于中心地位 CRBN 介导的 IMiD 耐药途径，我们将通过以下方式快速启动我们的目标蛋白质组学工作 专注于开发 CRBN 及其下游效应子的靶向检测方法。与此同时，我们预计 通过我们的发现研究确定其他候选蛋白质，为此也将进行针对性测定 开发的。最后，该提案的联合研究员 Vincent Rajkumar 博士将提供以下样本的访问权限： 三项 NCI 赞助的临床试验专门设计用于观察 IMiD 的效果，从而验证 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 包括 CyTOF 在内的平台，我们将确保在提案期间保持敏捷性。 凭借已建立的先进基础设施、在 CAP/CLIA 检测开发方面经验丰富的人员， 专用仪器、高分析能力和用于质量控制、数据处理和的现有管道 生物信息学方面，拟建的梅奥诊所临床蛋白质组学中心有望成功发现和 验证多发性骨髓瘤中 IMiD 耐药性的蛋白质组标记。

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.