P-4: Targeting activation of NFkB pathways in MM

P-4：MM 中 NFkB 通路的靶向激活

• 批准号: 7507317
• 负责人: Peter Leif Bergsagel
• 金额: $ 21.16万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7507317
• 关键词: 11q13; 4p16; 6p21; Affect; Bone Marrow; Categories; Cell Line; Cells; Chromosomes, Human, Pair 3; Clinical Trials; Correlative Study; Critical Pathways; Cyclin D1; Disease; Event; Gene Mutation; Genes; Genetic; Glucocorticoids; Goals; Growth; Immunoglobulin Genes; In Vitro; Ligands; Malignant - descriptor; Multiple Myeloma; Mutate; Mutation; NF-kappa B; NFKB Activation Pathway; Oncogenes; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Pre-Clinical Model; Process; Recurrence; Sampling; Signal Transduction; Subgroup; TNF receptor-associated factor 3; TP53 gene; Therapeutic; Therapeutic Index; Trisomy; Work; c-myc Genes; in vivo; in vivo Model; inhibitor/antagonist; neoplastic cell; novel; pre-clinical; preclinical study; response; small molecule; tumor; tumor progression; tumorigenesis

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.

多发性骨髓瘤是一种临床和遗传异质性疾病。一半的患者 超二倍体，另一半具有五种复发性免疫球蛋白基因易位之一。无论是 在某些情况下，这些被认为是代表主要的遗传事件，其后果是基因调控失调。 细胞周期蛋白D基因的表达。随后的肿瘤进展伴随RAS的激活突变， MYC的继发易位和p53的失活突变。最近，我们发现了一个 主要激活非经典NFkB途径的混杂突变阵列。最常见的 在~ 13%的MM患者中TRAF 3失活，这似乎表明患者对TRAF 3的应答较低。 糖皮质激素和对蛋白酶抑制剂的高反应。肿瘤获得如此多的突变 对这一单一途径的关注突出了其对MM细胞的至关重要性。我们假设在 大多数患者由于骨髓中的配体依赖性相互作用而激活该途径 微环境中的突变，只有一小部分（约20%）的患者获得突变引起的组成性激活。 我们建议解剖出的机制，导致激活的经典和非经典NF κ B MM患者的通路。我们假设，无论是在存在配体依赖，以及配体不依赖 激活这一通路，将有一个有利的治疗指数，其抑制。我们 建议使用小分子抑制剂研究特异性靶向抑制的功能后果， 相关的临床前模型。最后，我们建议将靶向NFkB通路引入临床试验 在临床前研究中显示出希望的抑制剂。