Oncogenomics to Identify and Validate Novel Targeted Therapies in Multiple Myelom

项目总结（见说明书）：我们利用骨髓环境下多发性骨髓瘤（MM）细胞的体外和体内模型来证明新型药物靶向肿瘤细胞、宿主相互作用和骨髓微环境克服传统耐药性的分子机制。然后，我们迅速将这些实验室发现转化为临床，导致FDA在过去五年中批准了六种新的治疗方法；重要的是，作为这些进展的直接结果，MM患者的中位生存期已从3年延长至7年。我们在体外和体内联合硼替佐米与来那度胺的临床前研究显示出协同MM细胞毒性，我们在新诊断患者中的衍生临床试验显示出显著的反应；总之，这些数据为项目1提出的临床研究提供了依据。我们假设，在项目2和4中，通过广泛的肿瘤基因组分析发现的遗传变化代表了MM的新治疗靶点。在这个项目中，我们将使用我们强大的人类MM模型系统来严格验证这些新靶点在MM细胞生长、存活和耐药性中的作用；并评估这些靶点的治疗潜力，无论是单独还是与现有的和新兴的MM治疗药物联合。我们将使用针对这些靶点的高通量shrna检测来识别那些调节MM细胞生长和体外存活的靶点（Specific Aim 1）；利用我们在骨髓环境下的人MM体外和体内模型，验证选定的分子靶点调节MM细胞生长、存活和耐药性的功能作用（Specific Aim 2）；并评估针对这些经过验证的新分子靶点的潜在治疗药物的影响，单独或联合治疗MM （Specific Aim 3）。因此，该提案将确定MM的下一代靶向治疗方法。

PROJECT SUMMARY (See instructions): We have utilized our in vitro and in vivo models of the multiple myeloma (MM) cell in the BM milieu to demonstrate the molecular mechanisms whereby novel agents target tumor cells, host interactions, and the BM microenvironment to overcome conventional drug resistance. We have then rapidly translated these laboratory findings to the clinic leading to FDA approvals of six novel treatments in the past five years; importantly, the median survival of MM patients has been extended from 3 to 7 years as a direct result of these advances. Our preclinical in vitro and in vivo efforts combining bortezomib with lenalidomide demonstrated synergistic MM cytotoxicity, and our derived clinical trials in newly diagnosed patients showed remarkable response; together, these data provided the rationale for the proposed clinical study in Project 1. We hypothesize that genetic changes identified using extensive oncogenomic profiling in Projects 2 and 4 represent novel therapeutic targets in MM. In this Project, we will use our robust human MM model systems to stringently validate the role of these novel targets in MM cell growth, survival, and drug resistance; and assess the therapeutic potential of these targets, both alone and in combination with established and emerging MM therapeutics. We will use a high-throughput shRNA-based assay directed at these targets to identify those regulating MM cell growth and survival in vitro (Specific Aim 1); 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 2); and evaluate the impact of potential therapeutic agents directed against these validated novel molecular targets, alone and in combination in MM (Specific Aim 3). This proposal will therefore identify the next generation of targeted therapies in MM.