P-4: Targeting activation of NFkB pathways in MM

P-4：MM 中 NFkB 通路的靶向激活

• 批准号: 8382445
• 负责人: Peter Leif Bergsagel
• 金额: $ 28.3万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8382445
• 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; 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。一半的病人都有