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Molecular Pathogenesis of Multiple Myeloma

多发性骨髓瘤的分子发病机制

基本信息

批准号：
8250027
负责人：
Peter Leif Bergsagel
金额：
$ 32.2万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-06-01 至 2014-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8250027
关键词：
11q13 4p16 6p21 American American Cancer Society Animal Model Bortezomib CCND1 gene Cell Line Chromosomal translocation Chromosomes, Human, Pair 3 Cyclin D1 DNA Development Dexamethasone Diagnosis Disease Disease Progression Drug effect disorder Drug resistance Event FGFR3 gene Future Gene Expression Gene Mutation Genetic Genetic Models Genomics Immunoglobulin Genes Immunoglobulins Individual Intervention Laboratories Lead Malignant Neoplasms Molecular Multiple Myeloma Mus Mutation NF-kappa B Other Genetics Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Recurrence Relapse Relative (related person)Role Sampling TNF receptor-associated factor 3 Thalidomide Therapeutic Time Transgenic Mice Trisomy base c-myc Genes cancer diagnosis clinically significant design drug development lenalidomide mouse model novel response tumor tumor progression

项目摘要

Project Summary In 2007, the American Cancer Society estimates that 19,900 will be diagnosed with, and that 10,790 will die from multiple myeloma (MM). Recent improvements in the treatment of patients have been empiric, and the molecular basis for the particular sensitivity of MM patients to bortezomib, thalidomide and lenalidomide is unclear. This project will use a genetic approach to explore the molecular basis of myeloma disease initiation, progression, drug response and drug resistance. Previous studies have shown that there are two main genetic subtypes of MM, one characterized by recurrent immunoglobulin gene translocations involving five loci (4p16 FGFR3/MMSET, 16q23 c-maf, 20q11 mafB, 11q13 CCND1, 6p21 CCND3); and the other lacking these translocations, and characterized by hyperdiploidy, with multiple trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19 and 21. Secondary genetic events common to both MM subtypes include activating mutations of ras, inactivating mutations of p53, and translocations of myc. Recently, through an integrated genomic analysis of gene expression and DNA copy level changes in myeloma patients and cell lines, we identified a promiscuous array of mutations that activate the non canonical NFkB pathway in ~20% of MM patients, predominantly those without hyperdiploidy. Moreover, we found that patients with constitutive activation of the NFkB pathway seem to be particularly sensitive to bortezomib treatment. We will explore the clinical significance of these mutations in terms of disease progression, drug response and drug resistance. We will functionally validate the consequences of activation of the non-canonical NFkB pathway in MM using cell line and animal models. Finally, we will take a directed approach to the identification of novel genetic events associated with disease progression. To accomplish this, we will analyze paired samples from patients taken before and after the development of disease progression. Altogether, we anticipate that the results of these studies will provide the basis for individualized therapy, and rational combination and sequencing of existing drugs, and will identify the targets for future drug development efforts.

项目总结