Genomics and Proteomics

高通量基因组生物技术的应用在很大程度上加速了多发性骨髓瘤(MM)分子异质性的阐明。鉴于基因表达谱(GEP)在全疗法2方案的350多名患者和全疗法3方案的450多名患者中取得了成功，他们已经用这项技术进行了研究，并且需要更好地了解MM的细胞和分子生物学，包括其微环境(ME)，以便开发有效靶向肿瘤细胞和微环境的治疗方法。我们建议继续并扩大这项工作，适用于项目1中所有进入临床试验的新诊断患者，以及全面疗法3、4的患者。在项目2中，5名正在经历复发的患者进入了新型同种异体自然杀伤细胞疗法的挽救试验。随着蛋白质组学技术的最新进展，我们还将对大多数患者的肿瘤细胞进行蛋白质组学分析(PP)。在项目3和项目4中，GEP一直是并将成为我们研究MM肿瘤细胞操纵骨髓ME的不可或缺的工具。这个基因组和蛋白质组学核心的主要目标是提供一个高度专业化的、分子共享的资源，为现有的研究项目服务。这一资源结合了Donna D.和Donald M.Lambert骨髓瘤遗传学实验室以及温斯罗普·P·洛克菲勒癌症研究所骨髓瘤研究和治疗研究所南希和斯蒂芬骨髓瘤蛋白质组学大实验室的设施和专业知识。该核心的目标将通过以下具体目标来实现：具体目标1：通过提供临床材料和来自体外和体内模型的细胞的基因组和蛋白质组图谱，协助开展每个P01项目的研究。具体地说，GEP和PP将在患者样本以及体内动物模型研究和体外细胞培养研究的样本上进行。具体目标2：维护和关联来自基因组和蛋白质组研究的数据。GEP和PP数据的数据挖掘和统计分析，与Core A和Project 3的生物统计学成分相结合，将为MM治疗和风险分层预测模型的开发提供基础。在Project 4中，GEP和PP将有助于在体外模型系统中识别骨髓瘤细胞与破骨细胞和成骨细胞之间相互作用中改变的遗传路径。

Utilization of high-throughput genomic biotechnologies to a great extent accelerated the elucidation of the molecular heterogeneity of multiple myeloma (MM). In view of the success of gene expression profiling (GEP) of more than 350 patients on the Total Therapy 2 protocol and more than 450 patients on the Total Therapy 3 protocols who have been studied with this technique¿and the need to better understand the cellular and molecular biology of MM, including its microenvironment (ME), in order to develop treatments that effectively target tumor cells and the ME¿we propose to continue, and expand, this work on all newly diagnosed patients entering clinical trials in Project 1, as well as patients on Total Therapies 3,4, and 5 experiencing relapse who enter salvage trials with novel allogeneic natural killer cell therapies in Project 2. With the recent advances in proteomic technologies, we will also perform proteomic profiling (PP) on tumor cells from the majority of these patients. GEP has been and will be an indispensable tool in our investigation of MM tumor cell manipulation of the bone marrow ME in Project 3 and Project 4. The primary objective of this Genomics and Proteomics Core is to provide a highly specialized, molecular shared resource that will serve established research projects. This resource combines the facilities and expertise of the Donna D. and Donald M. Lambert Laboratory of Myeloma Genetics and the Nancy and Stephen Grand Laboratory for Myeloma Proteomics at the Myeloma Institute for Research and Therapy of the Winthrop P. Rockefeller Cancer Institute. The objective of this Core will be achieved through the following specific aims: Specific Aim 1: Assist in the conduct of research of each P01 project by providing genomic and proteomic profiling of clinical material and cells derived from in vitro and in vivo models. Specifically, GEP and PP will be performed on patient samples and on samples from in vivo animal model studies and in vitro cell culture studies. Specific Aim 2: Maintain and correlate data from the genomic and proteomic studies. Data mining and statistical analyses of GEP and PP data in collaboration with the biostatistical components of Core A and Project 3 will provide the basis for the development of predictive models for treatment and risk stratification of MM. In Project 4, GEP and PP will help identify genetic pathways altered in the interaction between myeloma cells and osteoclasts and osteoblasts in in vitro model systems.