title: Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy.
abstract: 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.
authors.affiliation: Comprehensive Cancer Center, Mayo Clinic, 13400 E Shea Blvd, Scottsdale, AZ, 85259, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.forename: Geoffrey M
authors.initials: GM
authors.lastname: Matthews
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Garbitt
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Palmer
authors.forename: Jake
authors.initials: J
authors.lastname: Shortt
authors.forename: Marcus
authors.initials: M
authors.lastname: Lefebure
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage; D001897:Boronic Acids / Q000008:administration & dosage / Q000494:pharmacology; D000069286:Bortezomib; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D016259:Genes, myc; D006801:Humans; D051379:Mice; D020297:Mice, Congenic; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000097:blood / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D009194:Myeloma Proteins / Q000378:metabolism; D009368:Neoplasm Transplantation; D011237:Predictive Value of Tests; D011719:Pyrazines / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D009194:Myeloma Proteins; D011719:Pyrazines; D000069286:Bortezomib