Project 3. Oncogenomics to identify and validate novel targeted therapies in myeloma

项目概要（项目3） 我们长期以来的重点是了解多发性骨髓瘤（MM）细胞-骨髓基质细胞 （BMSC）相互作用。我们利用骨髓环境中MM细胞的体外和体内模型， 鉴定支持骨髓瘤细胞生长、存活和耐药性的分子靶点和途径， 实施有效的基于分子的治疗，对MM患者的生存有显著影响。 重要的是，我们的研究不是关注单个靶点，而是整合各种基因组和表观基因组， 参数已确定基因调控网络的基本机制，负责 持续MM细胞生长，尽管单一靶向治疗。这些反复出现的重要网络图案 在更大的调控网络中形成功能节点，并被认为是导致疾病的关键 MM和其他癌症中的基因组改变。我们假设异常的分子网络驱动了 MM进展;赋予肿瘤细胞生长和存活优势;并影响临床结果;以及 这种回路的中断将具有治疗意义。在这个项目中，我们强大的人类MM模型 系统将被用来严格验证新的调节电路的作用， 在项目1和2中具有生物学/预后意义或在项目4中与疾病进展有关;以及 评估靶向这些回路的治疗潜力，无论是单独还是与已建立的 新兴的MM疗法。我们将利用我们先进的生物信息学分析方法， 骨髓瘤中失调的调控网络以及合并和/或基因特异性CRISPR筛选，以评估 候选监管网络（具体目标1a、B）每个组成部分的功能影响;验证 使用我们的方法，选择调节MM细胞生长、存活和耐药性的分子靶点， 骨髓环境中人MM的体外和体内模型（特定目标1c，d）;并评价 针对这些经验证的新型分子网络的潜在治疗剂单独和联合 具体目标2（Specific Aim 2）因此，这一建议将提高我们对调节电路的理解， 控制MM的肿瘤生长和进展，并开发MM的下一代靶向治疗。

Project Summary (Project 3) Our longstanding focus has been to understand the multiple myeloma (MM) cell- bone marrow stromal cell (BMSC) interactions. We have utilized our in vitro and in vivo models of the MM cell in the bone marrow milieu to identify molecular targets and pathways supporting myeloma cell growth, survival, and drug resistance, and implement effective molecularly-based therapies with dramatic effects on the survival of MM patients. Importantly, rather than focusing on individual targets, our studies integrating various genomic and epigenomic parameters have identified gene regulatory networks as the fundamental mechanisms responsible for continued MM cell growth, despite single targeted therapies. These recurrent and important network motifs form functional nodes in the larger regulatory networks, and are considered to be linchpins of disease causing genomic alterations in MM and other cancers. We hypothesize that aberrant molecular networks drive the progression of MM; confer tumor cell growth and survival advantage; and affect clinical outcome; and that disruption of such circuits will have therapeutic implications. In this project, our robust human MM model systems will be used to stringently validate the role of novel regulatory circuits identified to be of biologic/prognostic significance in Projects 1 and 2 or implicated in disease progression in Project 4; and assess the therapeutic potential of targeting these circuits, both alone and in combination with established and emerging MM therapeutics. We will use our advanced bioinformatic analytical methods to identify gene regulatory networks dysregulated in myeloma and a pooled and/or gene-specific CRISPR screen to evaluate functional impact of each component of the candidate regulatory networks (Specific Aim 1a,b); validate the functional role of selected molecular targets regulating MM cell growth, survival, and drug resistance using our in vitro and in vivo models of human MM in the bone marrow milieu (Specific Aim 1c,d); and evaluate the impact of potential therapeutic agents directed against these validated novel molecular networks, alone and in combination (Specific Aim 2). This proposal will thus improve our understanding of the regulatory circuitry that controls tumor growth and progression in MM, and to develop the next generation of targeted therapies in MM.