P-4: Targeting activation of NFkB pathways in MM

多发性骨髓瘤是一种临床和遗传异质性疾病。一半的患者有 超二倍体和另一半患有五种反复免疫球蛋白基因易位中的一种。在这两个地方 这些病例被认为代表了主要的遗传事件，其后果是 细胞周期蛋白D基因的表达。随后的肿瘤进展伴随着RAS的激活突变， MYC继发性易位和P53基因失活突变。最近我们发现了一种 主要激活非规范NFkB途径的杂乱突变阵列。最常见的 在-13%的多发性骨髓瘤患者中，TRAF3的失活似乎可以确定患者对 糖皮质激素，以及对蛋白酶抑制剂的高反应性。肿瘤获得如此多的突变 对这一单一途径的关注突出了它对多发性骨髓瘤细胞的关键重要性。我们假设在 大多数患者由于骨髓中的配体依赖的相互作用而激活该途径。 微环境，只有一小部分(~20%)的患者获得突变，导致结构性激活。 我们建议剖析导致正则和非正则NFkB激活的机制 多发性骨髓瘤患者的通路。我们假设在配体依赖的情况下，以及在配体非依赖的情况下 激活这一通路，就会有一个有利的治疗指标来抑制它。我们 建议研究使用小分子抑制剂的特异性靶向抑制的功能后果 相关的临床前模型。最后，我们建议将针对NFkB通路的研究引入临床试验。 抑制剂在临床前研究中显示出希望。

Multiple myeloma is a clinically and genetically heterogeneous disease. One half of patients have hyperdiploidy and the other half have one of five recurrent immunoglobulin gene translocations. In both cases these are felt to represent primary genetic events, with the consequence of dysregulation of the expression of a cyclin D gene. Subsequent tumor progression occurs with activating mutations of RAS, secondary translocations of MYC, and inactivating mutations of p53. Recently we have identified a promiscuous array of mutations that activate primarily the non-canonical NFkB pathway. The most common is inactivation of TRAF3 in -13% of MM patients that appears to identify patients with a low response to glucocorticoids, and a high response to proteasbme inhibitors. The tumor acquisition of so many mutations focused on this single pathway highlights its critical importance to the MM cell. We hypothesize that in the majority of patients the pathway is activated as a result of ligand-dependent interaction in the bone marrow microenvironment, and only a fraction (~20%) of patients acquire mutations causing constitutive activation. We propose to dissect out the mechanisms causing activation of the canonical and non-canonical NFkB pathway in MM patients. We hypothesize that both in the presence of ligand-dependent, as well as ligandindependent activation of this pathway, there will be a favorable therapeutic index to its inhibition. We propose to study the functional consequence of specific targeted inhibition using small molecule inhibitors in relevant pre-clinical models. Finally, we propose to introduce into clinical trials targeted NFkB pathway inhibitors showing promise in pre-clinical studies.