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 vivo downregulation of CCR2/CD180 mRNAs (>80%) was demonstrated in MV4,11 and KMS-11 xenograft tumors at efficacious AZD5153 doses. Consistent with in vitro rat blood data, an in vivo rat study confirmed greater inhibition of CCR2/CD180 mRNA in whole blood versus MYC at an efficacious dose. Finally, in vitro treatment 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.

Highlights

  • The number of epigenetic targets for cancer drug research and development is increasing as more encouraging data emerge [1]

  • Our data strongly support the use of chemokine receptor type 2 (CCR2) and CD180 mRNAs as whole blood PD biomarkers for BRD4 inhibitors, especially in situations where paired tumor biopsies are unavailable

  • They can be used as tumor-based PD biomarkers for hematologic tumors

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Summary

Introduction

The number of epigenetic targets for cancer drug research and development is increasing as more encouraging data emerge [1]. Inhibitors of DNA methyltransferase (i.e., azacitdine and decitabine) and histone deactylase (i.e., vorinostat and romidepsin) are already approved drugs for hematologic malignancies. Another epigenetic target that has elicited high interest recently is the BRD4/BET (Bromodomain and Extra-Terminal) protein family [2, 3]. These "epigenetic readers" include BRD 2, 3, 4, and T and are characterized by the presence of two tandem bromodomains. The binding of acetylated histones by the bromodomains promotes the recruitment of BET proteins to chromatin, resulting in the activation of gene transcription through their subsequent recruitment of positive transcription elongation factor (p-TEFb).

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