Oncogenomics to Identify and Validate Novel Targeted Therapies in Multiple Myelom

项目总结(参见说明书)：我们已经利用我们在BM环境中的多发性骨髓瘤(MM)细胞的体外和体内模型来展示新型药物靶向肿瘤细胞、宿主相互作用和BM微环境以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在过去五年批准了六种新的治疗方法；重要的是，这些进展直接导致MM患者的中位生存期从3年延长到7年。我们在体外和体内将Bortezomib与来那度胺结合的临床前努力显示了协同的MM细胞毒性，我们在新诊断患者中进行的派生临床试验显示了显著的反应；总之，这些数据为项目1中拟议的临床研究提供了理论基础。我们假设，在项目2和4中使用广泛的癌基因组图谱确定的基因变化代表MM的新治疗靶点。在本项目中，我们将使用我们强大的人类MM模型系统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，无论是单独使用还是与现有的和新兴的MM治疗方法结合使用。我们将使用针对这些靶点的高通量shRNA分析来确定在体外调控MM细胞生长和存活的那些分子靶点(特定目标1)；使用我们在骨髓环境中建立的人MM的体外和体内模型来验证选定的调控MM细胞生长、存活和耐药性的分子靶点的功能作用(特定目标2)；以及评估针对这些经过验证的新分子靶点的潜在治疗剂对MM的影响，单独和联合使用这些新的分子靶点(特定目标3)。因此，该提案将确定MM的下一代靶向疗法。

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.