title: Applying ⁸⁹Zr-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 (89)Zr-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 (89)Zr-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.
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Michael G
authors.initials: MG
authors.lastname: Doran
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Carnazza
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Steckler
authors.affiliation: Department of Radiation Oncology, University of Michigan , 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, United States.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Spratt
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco , 185 Berry Street, Lobby 6 Suite 350, San Francisco, California 94143, United States.
authors.forename: Charles
authors.initials: C
authors.lastname: Truillet
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: John
authors.initials: J
authors.lastname: Wongvipat
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Charles L
authors.initials: CL
authors.lastname: Sawyers
authors.affiliation: Department of Radiology, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.|Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center , 1275 York Avenue, New York, New York 10065, United States.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lewis
authors.affiliation: Department of Radiology and Biomedical Imaging, University of California San Francisco , 185 Berry Street, Lobby 6 Suite 350, San Francisco, California 94143, United States.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Evans
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D006801:Humans; D008223:Lymphoma / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000473:pathology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D019275:Radiopharmaceuticals; D011990:Receptors, Transferrin / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D015040:Zirconium / Q000737:chemistry*; D000092468:Bromodomain Containing Proteins
chemical_list: D051548:Histone Acetyltransferases; D056488:Histone Chaperones; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D019275:Radiopharmaceuticals; D011990:Receptors, Transferrin; D014168:Transferrin; D015040:Zirconium; C402649:BRD1 protein, human; D000092468:Bromodomain Containing Proteins
keywords: BRD4; MYC; PET; lymphoma; prostate cancer; transferrin receptor