The drug treatment of multiple myeloma is rapidly evolving, with four active classes of drugs (alkylating agents, glucocorticoids, proteasome inhibitors and Imids) being used in combinations with remarkable efficacy. Despite a high rate of remission, relapses still occur. This project seeks to use a novel transgenic Vk*MYC mouse model of myeloma to understand the molecular mechanism underlying drug response and optimize the drug treatment of patients with multiple myeloma (MM). Presumably because of its pathogenic fidelity the Vk*MYC model results in a tumor with close phenotypic fidelity to human MM, characterized by indolent bone marrow localized monoclonal plasma cells that respond to drugs much like human MM. We hypothesize that many fundamental aspects of MM cell biology are conserved between mouse and human MM, including important shared aspects of normal plasma cell biology. We propose to use our ability to manipulate the Vk*MYC MM genome in a controlled fashion in order to identify genetic changes associated with drug resistant MM that will be generated in vivo. We will then take a comparative pharmaco-oncogenomic approach and will query existing human MM genomic datasets for relevance of genetic changes identified in the mouse to human MM drug response. We will identify the genetic (DNA copy and GEP) changes in paired samples from patients before and after relapse from drug treatment and compare to similarly matched mouse samples. We will validate the relevance to in vivo drug resistance of the genetic changes identified. We will use lentiviral shRNA to target these genetic changes in Vk*MYC MM cells transplanted into recipient mice, and determine their relative drug sensitivity. In addition to examining the role of these genetic modifiers of drug response, we will examine pharmacologic modifiers of drug response implicated in clinical studies as a positive control for future studies. We will use response rate and time to progression in Vk*MYC MM to study in vivo drug combinations with proteasome inhibitors, seeking pre-clinical evidence of synergy in this model to support its use for the pre- clinical evaluations of combinations for use in the treatment of MM patients. In conclusion this proposal takes advantage of a novel faithful mouse model amenable to rapid genetic manipulation to understand and improve the drug treatment of MM patients

Public Health Relevance

Multiple myeloma is an incurable cancer. This project seeks to use a new mouse model to develop better therapies with which to treat patients.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Alley, Michael C
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Mayo Clinic, Arizona
United States
Zip Code
Affer, M; Chesi, M; Chen, W D et al. (2014) Promiscuous MYC locus rearrangements hijack enhancers but mostly super-enhancers to dysregulate MYC expression in multiple myeloma. Leukemia 28:1725-35
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
Matthews, G M; Lefebure, M; Doyle, M A et al. (2013) Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma. Cell Death Dis 4:e798
Chesi, Marta; Matthews, Geoffrey M; Garbitt, Victoria M et al. (2012) Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy. Blood 120:376-85
Keats, Jonathan J; Chesi, Marta; Egan, Jan B et al. (2012) Clonal competition with alternating dominance in multiple myeloma. Blood 120:1067-76
Suzuki, Erika; Demo, Susan; Deu, Edgar et al. (2011) Molecular mechanisms of bortezomib resistant adenocarcinoma cells. PLoS One 6:e27996
Kumar, Shaji K; Lacy, Martha Q; Hayman, Suzanne R et al. (2011) Lenalidomide, cyclophosphamide and dexamethasone (CRd) for newly diagnosed multiple myeloma: results from a phase 2 trial. Am J Hematol 86:640-5
Rajkumar, S Vincent; Gahrton, Gosta; Bergsagel, P Leif (2011) Approach to the treatment of multiple myeloma: a clash of philosophies. Blood 118:3205-11
Cavo, Michele; Rajkumar, S Vincent; Palumbo, Antonio et al. (2011) International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are candidates for autologous stem cell transplantation. Blood 117:6063-73
Munshi, Nikhil C; Anderson, Kenneth C; Bergsagel, P Leif et al. (2011) Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood 117:4696-700

Showing the most recent 10 out of 31 publications