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.

Public Health Relevance

Multiple myeloma is a deadly cancer diagnosed in 20,000 Americans annually. This proposal seeks to understand the specific molecular causes that lead to the formation, and ultimate progression of this disease. This will help us to design more active and less toxic therapies.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA133966-04
Application #
8250027
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Forry, Suzanne L
Project Start
2009-06-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$322,040
Indirect Cost
$120,765
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
153665211
City
Scottsdale
State
AZ
Country
United States
Zip Code
85259
Mishra, Aniket; Macgregor, Stuart (2015) VEGAS2: Software for More Flexible Gene-Based Testing. Twin Res Hum Genet 18:86-91
Affer, Maurizio; Chesi, Marta; Chen, Wei-Dong G et al. (2014) Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia 28:1725-1735
Bergsagel, P Leif; Mateos, Maria-Victoria; Gutierrez, Norma C et al. (2013) Improving overall survival and overcoming adverse prognosis in the treatment of cytogenetically high-risk multiple myeloma. Blood 121:884-92
Keats, Jonathan J; Chesi, Marta; Egan, Jan B et al. (2012) Clonal competition with alternating dominance in multiple myeloma. Blood 120:1067-76
Kuehl, W Michael; Bergsagel, P Leif (2012) Molecular pathogenesis of multiple myeloma and its premalignant precursor. J Clin Invest 122:3456-63
Kumar, Shaji; Fonseca, Rafael; Ketterling, Rhett P et al. (2012) Trisomies in multiple myeloma: impact on survival in patients with high-risk cytogenetics. Blood 119:2100-5
Chesi, Marta; Bergsagel, P Leif (2011) Many multiple myelomas: making more of the molecular mayhem. Hematology Am Soc Hematol Educ Program 2011:344-53
Bergsagel, P Leif; Kuehl, W Michael (2011) Comprehensive identification of somatic mutations in chronic lymphocytic leukemia. Cancer Cell 20:5-7
Nair, Jayakumar R; Carlson, Louise M; Koorella, Chandana et al. (2011) CD28 expressed on malignant plasma cells induces a prosurvival and immunosuppressive microenvironment. J Immunol 187:1243-53
Chapman, Michael A; Lawrence, Michael S; Keats, Jonathan J et al. (2011) Initial genome sequencing and analysis of multiple myeloma. Nature 471:467-72

Showing the most recent 10 out of 35 publications