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。这项研究的中心假设是，抑制特定的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。我们在这项提案中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，并在临床上推进这一信息。具体目标1将解决骨髓瘤中最近发现的NFKappaB混杂突变的影响及其与蛋白酶体抑制剂敏感性的关系。目标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。将应用靶向可药用基因组的10，000个siRNA文库。特异性目标3的结构能够快速验证特异性目标2中优先考虑的候选基因作为骨髓瘤细胞中的致敏靶点在功能上相关的假设。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遗传数据来快速验证优先候选物的临床重要性，以及先前描述的硼替佐米靶点。我们整个研究的最终目标将是产生新的增敏剂药物，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.