The Molecular Basis for Bortezomib Activity

描述（由申请人提供）：我们的长期目标是改善骨髓瘤的治疗方法。该研究的中心假设是抑制特定基因靶点将调节骨髓瘤细胞对硼替佐米和其他蛋白酶体抑制剂的敏感性。我们的目标是应用先进的功能基因组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，并将这些信息推进临床。特异性目标1将解决最近发现的NFKappaB混杂突变在骨髓瘤中的影响及其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筛选来鉴定使骨髓瘤细胞敏感或保护骨髓瘤细胞免受硼替佐米或pr -171诱导的细胞死亡的关键基因或途径。一个由10000个靶向药物基因组的siRNA组成的文库将被应用。特异性Aim 3的结构是为了快速验证特异性Aim 2中优先考虑的候选基因在骨髓瘤细胞中作为致敏靶点的功能相关的假设。在Specific Aim 4中，我们将使用来自临床试验和临床数据库的组织和遗传数据来快速验证优先候选药物和先前描述的硼替佐米靶点的临床重要性。我们整个研究的最终目标是产生新的增敏药物用于联合治疗，以提高硼替佐米或其他PI治疗的临床成功率。

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.