Applying (89)Zr-transferrin to study the pharmacology of inhibitors to BET bromodomain containing proteins Journal Article


Authors: Doran, M. G.; Carnazza, K. E.; Steckler, J. M.; Spratt, D. E.; Truillet, C.; Wongvipat, J.; Sawyers, C. L.; Lewis, J. S.; Evans, M. J.
Article Title: Applying (89)Zr-transferrin to study the pharmacology of inhibitors to BET bromodomain containing proteins
Abstract: Chromatin modifying proteins are attractive drug targets in oncology, given the fundamental reliance of cancer on altered transcriptional activity. Multiple transcription factors can be impacted downstream of primary target inhibition, thus making it challenging to understand the driving mechanism of action of pharmacologic inhibition of chromatin modifying proteins. This in turn makes it difficult to identify biomarkers predictive of response and pharmacodynamic tools to optimize drug dosing. In this report, we show that 89Zr-transferrin, an imaging tool we developed to measure MYC activity in cancer, can be used to identify cancer models that respond to broad spectrum inhibitors of transcription primarily due to MYC inhibition. As a proof of concept, we studied inhibitors of BET bromodomain containing proteins, as they can impart antitumor effects in a MYC dependent or independent fashion. In vitro, we show that transferrin receptor biology is inhibited in multiple MYC positive models of prostate cancer and double hit lymphoma when MYC biology is impacted. Moreover, we show that bromodomain inhibition in one lymphoma model results in transferrin receptor expression changes large enough to be quantified with 89Zr-transferrin and positron emission tomography (PET) in vivo. Collectively, these data further underscore the diagnostic utility of the relationship between MYC and transferrin in oncology, and provide the rationale to incorporate transferrin-based PET into early clinical trials with bromodomain inhibitors for the treatment of solid tumors. © 2016 American Chemical Society.
Keywords: controlled study; protein expression; treatment response; unclassified drug; nonhuman; solid tumor; positron emission tomography; mouse; animal tissue; enzyme inhibition; pharmacodynamics; image analysis; clinical assessment; animal experiment; animal model; in vivo study; antineoplastic activity; in vitro study; cancer model; prostate cancer; drug mechanism; isotope labeling; diagnostic value; chromatin; myc protein; lymphoma; inhibition kinetics; tracer; molecular biology; pet; myc; clinical trial (topic); transferrin receptor; brd4; human; male; priority journal; article; bromodomain inhibitor; 2 methoxy n (1,2,3,4 tetrahydro 3 methyl 2 oxo 6 quinazolinyl)benzenesulfonamide; transferrin zr 89
Journal Title: Molecular Pharmaceutics
Volume: 13
Issue: 2
ISSN: 1543-8384
Publisher: American Chemical Society  
Date Published: 2016-02-01
Start Page: 683
End Page: 688
Language: English
DOI: 10.1021/acs.molpharmaceut.5b00882
PROVIDER: scopus
PMCID: PMC4738321
PUBMED: 26725682
DOI/URL:
Notes: Article -- Export Date: 3 March 2016 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Charles L Sawyers
    153 Sawyers
  2. Jason S Lewis
    242 Lewis
  3. Michael G. Doran
    17 Doran