title: Identification of CCR2 and CD180 as Robust Pharmacodynamic Tumor and Blood Biomarkers for Clinical Use with BRD4/BET Inhibitors.
abstract: Purpose:AZD5153 is a novel BRD4/BET inhibitor with a distinctive bivalent bromodomain binding mode. To support its clinical development, we identified pharmacodynamic (PD) biomarkers for use in clinical trials to establish target engagement.Experimental Design:CCR2 and CD180 mRNAs, initially identified from whole transcriptome profiling, were further evaluated by quantitative PCR in hematologic cell lines, xenografts, and whole blood from rat, healthy volunteers, and patients with cancer. MYC and HEXIM1 mRNAs were also evaluated.Results:RNA-sequencing data showed consistent decreases in CCR2/CD180 expression across multiple hematologic cell lines upon AZD5153 treatment. Evaluation of dose dependence in MV4,11 cells confirmed activity at clinically relevant concentrations.In vivodownregulation of CCR2/CD180 mRNAs (>80%) was demonstrated in MV4,11 and KMS-11 xenograft tumors at efficacious AZD5153 doses. Consistent within vitrorat blood data, anin vivorat study confirmed greater inhibition of CCR2/CD180 mRNA in whole blood versus MYC at an efficacious dose. Finally,in vitrotreatment of whole blood from healthy volunteers and patients with cancer demonstrated, in contrast to MYC, almost complete downregulation of CCR2/CD180 at predicted clinically achievable concentrations.Conclusions:Our data strongly support the use of CCR2 and CD180 mRNAs as whole blood PD biomarkers for BRD4 inhibitors, especially in situations where paired tumor biopsies are unavailable. In addition, they can be used as tumor-based PD biomarkers for hematologic tumors. MYC mRNA is useful as a hematologic tumor-based biomarker but suboptimal as a whole blood biomarker. Utility of HEXIM1 mRNA may be limited to higher concentrations.Clin Cancer Res; 23(4); 1025-35. ©2017 AACR.
authors.affiliation: Translational Sciences, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts. Tammie.Yeh@astrazeneca.com.
authors.forename: Tammie C
authors.initials: TC
authors.lastname: Yeh
authors.affiliation: Translational Sciences, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors.forename: Greg
authors.initials: G
authors.lastname: O'Connor
authors.affiliation: Biosciences, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors.forename: Philip
authors.initials: P
authors.lastname: Petteruti
authors.affiliation: Biosciences, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors.forename: Austin
authors.initials: A
authors.lastname: Dulak
authors.affiliation: Biosciences, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors.forename: Maureen
authors.initials: M
authors.lastname: Hattersley
authors.affiliation: Translational Sciences, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors.forename: J Carl
authors.initials: JC
authors.lastname: Barrett
authors.affiliation: Biosciences, Oncology Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, Massachusetts.
authors.forename: Huawei
authors.initials: H
authors.lastname: Chen
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic; D019337:Hematologic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D006574:Heterocyclic Compounds, 2-Ring / Q000008:administration & dosage / Q000097:blood; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood; D016271:Proto-Oncogene Proteins c-myc / Q000097:blood; D011720:Pyrazoles; D011724:Pyridazines; D051381:Rats; D054390:Receptors, CCR2 / Q000097:blood*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays; D000092468:Bromodomain Containing Proteins
chemical_list: D015703:Antigens, CD; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D006574:Heterocyclic Compounds, 2-Ring; D009687:Nuclear Proteins; D010879:Piperazines; D016271:Proto-Oncogene Proteins c-myc; D011720:Pyrazoles; D011724:Pyridazines; D054390:Receptors, CCR2; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C515334:CCR2 protein, human; C092722:CD180 protein, human; C489427:MYC protein, human; C000621120:AZD5153