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

项目总结(项目3) 我们长期以来的重点一直是了解多发性骨髓瘤(MM)细胞-骨髓基质细胞 (BMSC)相互作用。我们已经在骨髓环境中使用了我们的MM细胞的体外和体内模型 确定支持骨髓瘤细胞生长、存活和耐药的分子靶点和途径 实施有效的基于分子的治疗，对多发性骨髓瘤患者的生存产生显著影响。 重要的是，我们的研究不是集中在单个目标上，而是整合了各种基因组和表观基因组 参数已经确定基因调控网络是负责 尽管进行了单一靶向治疗，MM细胞仍在继续生长。这些反复出现的重要网络主题 在更大的调控网络中形成功能节点，被认为是致病的关键 多发性骨髓瘤和其他癌症的基因组改变。我们假设反常的分子网络驱动了 多发性骨髓瘤的进展；赋予肿瘤细胞生长和生存优势；并影响临床预后； 这种环路的中断将具有治疗意义。在这个项目中，我们的健壮人类MM模型 系统将被用来严格验证被确定为 在项目1和2中的生物学/预后意义或在项目4中涉及疾病进展；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和 新兴的多发性骨髓瘤疗法。我们将使用我们先进的生物信息学分析方法来鉴定基因 骨髓瘤的调控网络失调和一项集合和/或基因特异性CRISPR筛查 候选监管网络的每个组成部分的功能影响(具体目标1a，b)；验证 利用OUR调控MM细胞生长、存活和耐药性的选定分子靶点的功能作用 骨髓环境中人多发性骨髓瘤的体外和体内模型(特异性靶点1c，d)； 潜在治疗药物对这些有效的新分子网络的影响，单独和在 组合(具体目标2)。因此，这一提议将提高我们对调节电路的理解 控制MM中的肿瘤生长和进展，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.