title: Replication Study: BET bromodomain inhibition as a therapeutic strategy to target c-Myc.
abstract: In 2015, as part of the Reproducibility Project: Cancer Biology, we published a Registered Report (Kandela et al., 2015) that described how we intended to replicate selected experiments from the paper "BET bromodomain inhibition as a therapeutic strategy to target c-Myc" (Delmore et al., 2011). Here we report the results of those experiments. We found that treatment of human multiple myeloma (MM) cells with the small-molecular inhibitor of BET bromodomains, (+)-JQ1, selectively downregulatedMYCtranscription, which is similar to what was reported in the original study (Figure 3B; Delmore et al., 2011). Efficacy of (+)-JQ1 was evaluated in an orthotopically xenografted model of MM. Overall survival was increased in (+)-JQ1 treated mice compared to vehicle control, similar to the original study (Figure 7E; Delmore et al., 2011). Tumor burden, as determined by bioluminescence, was decreased in (+)-JQ1 treated mice compared to vehicle control; however, while the effect was in the same direction as the original study (Figure 7C-D; Delmore et al., 2011), it was not statistically significant. The opportunity to detect a statistically significant difference was limited though, due to the higher rate of early death in the control group, and increased overall survival in (+)-JQ1 treated mice before the pre-specified tumor burden analysis endpoint. Additionally, we evaluated the (-)-JQ1 enantiomer that is structurally incapable of inhibiting BET bromodomains, which resulted in a minimal impact onMYCtranscription, but did not result in a statistically significant difference in tumor burden or survival distributions compared to treatment with (+)-JQ1. Finally, we report meta-analyses for each result.
authors.affiliation: Developmental Therapeutics Core, Northwestern University, Evanston, United States.
authors.forename: Fraser
authors.initials: F
authors.lastname: Aird
authors.affiliation: Developmental Therapeutics Core, Northwestern University, Evanston, United States.
authors.forename: Irawati
authors.initials: I
authors.lastname: Kandela
authors.affiliation: Developmental Therapeutics Core, Northwestern University, Evanston, United States.
authors.forename: Christine
authors.initials: C
authors.lastname: Mantis
authors.affiliation: Developmental Therapeutics Core, Northwestern University, Evanston, United States.
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001381:Azepines / Q000008:administration & dosage*; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000235:genetics*; D015203:Reproducibility of Results; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic; D014230:Triazoles / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D001381:Azepines; D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; D014230:Triazoles; C561695:(+)-JQ1 compound; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C489427:MYC protein, human
keywords: Reproducibility Project: Cancer Biology; bromodomain inhibitor; cancer biology; human; metascience; mouse; myeloma; replication; reproducibility