TY - JOUR
T1 - Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy
AU - Chesi, Marta
AU - Matthews, Geoffrey M.
AU - Garbitt, Victoria M.
AU - Palmer, Stephen E.
AU - Shortt, Jake
AU - Lefebure, Marcus
AU - Stewart, A. Keith
AU - Johnstone, Ricky W.
AU - Leif Bergsagel, P.
PY - 2012/7/12
Y1 - 2012/7/12
N2 - The attrition rate for anticancer drugs entering clinical trials is unacceptably high. For multiple myeloma (MM), we postulate that this is because of preclinical models that overemphasize the antiproliferative activity of drugs, and clinical trials performed in refractory end-stage patients. We validate the Vk*MYC transgenic mouse as a faithful model to predict single-agent drug activity in MM with a positive predictive value of 67% (4 of 6) for clinical activity, and a negative predictive value of 86% (6 of 7) for clinical inactivity. We identify 4 novel agents that should be prioritized for evaluation in clinical trials. Transplantation of Vk*MYC tumor cells into congenic mice selected for a more aggressive disease that models end-stage drug-resistant MM and responds only to combinations of drugs with single-agent activity in untreated Vk*MYC MM. We predict that combinations of standard agents, histone deacetylase inhibitors, bromodomain inhibitors, and hypoxia-activated prodrugs will demonstrate efficacy in the treatment of relapsed MM.
AB - The attrition rate for anticancer drugs entering clinical trials is unacceptably high. For multiple myeloma (MM), we postulate that this is because of preclinical models that overemphasize the antiproliferative activity of drugs, and clinical trials performed in refractory end-stage patients. We validate the Vk*MYC transgenic mouse as a faithful model to predict single-agent drug activity in MM with a positive predictive value of 67% (4 of 6) for clinical activity, and a negative predictive value of 86% (6 of 7) for clinical inactivity. We identify 4 novel agents that should be prioritized for evaluation in clinical trials. Transplantation of Vk*MYC tumor cells into congenic mice selected for a more aggressive disease that models end-stage drug-resistant MM and responds only to combinations of drugs with single-agent activity in untreated Vk*MYC MM. We predict that combinations of standard agents, histone deacetylase inhibitors, bromodomain inhibitors, and hypoxia-activated prodrugs will demonstrate efficacy in the treatment of relapsed MM.
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U2 - 10.1182/blood-2012-02-412783
DO - 10.1182/blood-2012-02-412783
M3 - Article
C2 - 22451422
AN - SCOPUS:84864040412
SN - 0006-4971
VL - 120
SP - 376
EP - 385
JO - Blood
JF - Blood
IS - 2
ER -