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ABSTRACTGSK1322322 is a novel inhibitor of peptide deformylase (PDF) with good in vitroactivity against bacteria associated with community-acquired pneumonia and skin infections. We have characterized the in vivopharmacodynamics (PD) of GSK1322322 in immunocompetent animal models of infection with Streptococcus pneumoniaeand Haemophilus influenzae(mouse lung model) and with Staphylococcus aureus(rat abscess model) and determined the pharmacokinetic (PK)/PD index that best correlates with efficacy and its magnitude. Oral PK studies with both models showed slightly higher-than-dose-proportional exposure, with 3-fold increases in area under the concentration-time curve (AUC) with doubling doses. GSK1322322 exhibited dose-dependent in vivoefficacy against multiple isolates of S. pneumoniae, H. influenzae, and S. aureus. Dose fractionation studies with two S. pneumoniaeand S. aureusisolates showed that therapeutic outcome correlated best with the free AUC/MIC (fAUC/MIC) index in S. pneumoniae(R2, 0.83), whereas fAUC/MIC and free maximum drug concentration (fCmax)/MIC were the best efficacy predictors for S. aureus(R2, 0.9 and 0.91, respectively). Median daily fAUC/MIC values required for stasis and for a 1-log10reduction in bacterial burden were 8.1 and 14.4 for 11 S. pneumoniaeisolates (R2, 0.62) and 7.2 and 13.0 for five H. influenzaeisolates (R2, 0.93). The data showed that for eight S. aureusisolates, fAUC correlated better with efficacy than fAUC/MIC (R2, 0.91 and 0.76, respectively), as efficacious AUCs were similar for all isolates, independent of their GSK1322322 MIC (range, 0.5 to 4 μg/ml). Median fAUCs of 2.1 and 6.3 μg · h/ml were associated with stasis and 1-log10reductions, respectively, for S. aureus.

Triple-negative breast cancer (TNBC) and ovarian carcinomas (OvCas) with BRCA1promoter methylation (BRCA1meth) respond more poorly to alkylating agents compared to those bearing mutations in BRCA1and BRCA2(BRCAmut). This is a conundrum given the biologically equivalent homologous recombination deficiency (HRD) induced by these genetic and epigenetic BRCAperturbations. We dissected this problem through detailed genomic analyses of TNBC and OvCa cohorts and experimentation with patient-derived xenografts and genetically engineered cell lines. We found that despite identical downstream genomic mutational signatures associated with BRCA1meth and BRCAmut states, BRCA1meth uniformly associates with poor outcomes. Exposure of BRCA1meth TNBCs to platinum chemotherapy, either as clinical treatment of a patient or as experimental in vivo exposure of preclinical patient derived xenografts, resulted in allelic loss of BRCA1methylation and increased BRCA1expression and platinum resistance. These data suggest that, unlike BRCAmut cancers, where BRCAloss is a genetically “fixed” deficiency state, BRCA1meth cancers are highly adaptive to genotoxin exposure and, through reversal of promoter methylation, recover BRCA1expression and become resistant to therapy. We further found a specific augmented immune transcriptional signal associated with enhanced response to platinum chemotherapy but only in patients with BRCA-proficient cancers. We showed how integrating both this cancer immune signature and the presence of BRCAmutations results in more accurate predictions of patient response when compared to either HRD status or BRCAstatus alone. This underscores the importance of defining BRCAheterogeneity in optimizing the predictive precision of assigning response probabilities in TNBC and OvCa.