The Molecular Basis for Bortezomib Activity

描述(申请人提供)：我们的长期目标是提高骨髓瘤的治疗水平。这项研究的中心假设是，抑制特定的基因靶标将调节骨髓瘤细胞对Bortezomib和其他蛋白酶体抑制剂的敏感性。我们在这项建议中的目标是应用先进的功能基因组学策略来识别和快速验证候选基因在药物性能中的关键作用，并将这一信息推广到临床。具体目标1将解决最近发现的NFKappaB在骨髓瘤中的混杂突变的影响，以及它们与蛋白酶体抑制剂敏感性的关系。AIM 2将利用创新的高通量siRNA筛选来识别使骨髓瘤细胞敏感或保护其免受Bortezomib或PR-171诱导的细胞死亡的关键基因或途径。针对可药物基因组的10,000个siRNA文库将被应用。特定目标3的结构使得能够快速验证假设，即在特定目标2中优先考虑的候选基因在功能上与骨髓瘤细胞中的增敏靶标相关。在具体目标4中，我们将使用来自临床试验和临床数据库的组织和基因数据来快速验证优先候选药物和先前描述的波特佐米靶标的临床重要性。我们整个研究的最终目标将是开发出新的致敏药物，用于联合治疗，以提高Bortezomib或其他PI疗法的临床成功率。

DESCRIPTION (provided by applicant): Our long-range goal is to improve the therapy of Myeloma. The central hypothesis for the proposed research is that inhibition of specific gene targets will modulate the sensitivity of Myeloma cells to bortezomib and other proteasome inhibitors. Our objective in this proposal is to apply advanced functional genomic strategies to identify and rapidly validate the critical role of candidate genes in drug performance and advance this information clinically. Specific Aim 1 will address the influence of recently-identified promiscuous mutations of NFKappaB in Myeloma and their relationship to proteasome inhibitor sensitivity. Aim 2 will utilize an innovative high-throughput siRNA screen to identify critical genes or pathways which sensitize or protect Myeloma cells from bortezomib- or PR-171-induced cell death. A library of 10,000 siRNA targeting the druggable genome will be applied. Specific Aim 3 is structured to enable rapid validation of the hypothesis that the candidate genes prioritized in Specific Aim 2 are functionally relevant as sensitizing targets in Myeloma cells. In Specific Aim 4, we will use tissues and genetic data from clinical trials and clinical databases to rapidly validate the clinical importance of prioritized candidates, and previously-described targets of bortezomib. The ultimate goal of our entire study will be to generate new sensitizer drugs to be used in combination therapy to increase the clinical success rate of bortezomib or other PI therapy.