ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is associated with extensive dysregulation of the epigenome and epigenetic regulators, such as bromodomain and extraterminal motif (BET) proteins, have been suggested as potential targets for therapy. However, single-agent BET inhibition has shown poor efficacy in clinical trials, and no epigenetic approaches are currently used in PDAC. To circumvent the limitations of the current generation of BET inhibitors, we developed the compound XP-524 as an inhibitor of the BET protein BRD4 and the histone acetyltransferase EP300/CBP, both of which are ubiquitously expressed in PDAC tissues and cooperate to enhance tumorigenesis. XP-524 showed increased potency and superior tumoricidal activity than the benchmark BET inhibitor JQ-1 in vitro, with comparable efficacy to higher-dose JQ-1 combined with the EP300/CBP inhibitor SGC-CBP30. We determined that this is in part due to the epigenetic silencing of KRAS in vitro, with similar results observed using ex vivo slice cultures of human PDAC tumors. Accordingly, XP-524 prevented KRAS-induced, neoplastic transformation in vivo and extended survival in two transgenic mouse models of aggressive PDAC. In addition to the inhibition of KRAS/MAPK signaling, XP-524 also enhanced the presentation of self-peptide and tumor recruitment of cytotoxic T lymphocytes, though these lymphocytes remained refractory from full activation. We, therefore, combined XP-524 with an anti-PD-1 antibody in vivo, which reactivated the cytotoxic immune program and extended survival well beyond XP-524 in monotherapy. Pending a comprehensive safety evaluation, these results suggest that XP-524 may benefit PDAC patients and warrant further exploration, particularly in combination with immune checkpoint inhibition.
Subject(s)
Antineoplastic Agents/pharmacology , E1A-Associated p300 Protein/antagonists & inhibitors , Immune Checkpoint Inhibitors/pharmacology , Proteins/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/antagonists & inhibitors , Animals , Antineoplastic Agents/chemistry , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Line, Tumor , Disease Models, Animal , Drug Synergism , E1A-Associated p300 Protein/chemistry , Gene Expression Regulation , Humans , Kaplan-Meier Estimate , Mice , Models, Molecular , Molecular Conformation , Molecular Structure , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Proto-Oncogene Proteins p21(ras)/chemistry , Structure-Activity Relationship , Transcription Factors/genetics , Transcription Factors/metabolism , Treatment Outcome , Xenograft Model Antitumor AssaysABSTRACT
Objective To measure the in vitro antibacterial activity of tigecycline against carbapenems-resistant Acinetobacter calcoacetcus-Acinetobacter baumannii complex.Methods The isolated strains of carbapenems-resistant Acinetobacter calcoacetcus-Acinetobacter baumannii complex were collected in our hospital from December 2013 to February 2014.The MIC test strip was a-dopted to measure the MIC value of tigecycline.The break point adopted the judgment criteria published by FDA.Results All 61 strains of carbapenems-resistant Acinetobacter calcoacetcus-Acinetobacter baumannii complex had extremely high drug resistant rate to the commonly used antimicrobial agents.The sensitive rate of tigecycline was 80.3%,intermediation was 19.7% and no re-sistant strain was found in this study.MIC50 and MIC90 were 2 μg/mL and 3 μg/mL respectively.Conclusion Tigecycline has bet-ter in vitro antibacterial activity to the carbapenems-resistant Acinetobacter calcoacetcus-Acinetobacter baumannii complex isolated in our hospital.
