Noninvasive (89)Zr-transferrin PET shows improved tumor targeting compared with (18)F-FDG PET in MYC-overexpressing human triple-negative breast cancer Journal Article

Authors: Henry, K. E.; Dilling, T. R.; Abdel-Atti, D.; Edwards, K. J.; Evans, M. J.; Lewis, J. S.
Article Title: Noninvasive (89)Zr-transferrin PET shows improved tumor targeting compared with (18)F-FDG PET in MYC-overexpressing human triple-negative breast cancer
Abstract: The current standard for breast PET imaging is 18F-FDG. The heterogeneity of 18F-FDG uptake in breast cancer limits its utility, varying greatly among receptor status, histopathologic subtypes, and proliferation markers. 18F-FDG PET often exhibits nonspecific internalization and low specificity and sensitivity, especially with tumors smaller than 1 cm3. MYC is a protein involved in oncogenesis and is overexpressed in triple-negative breast cancer (TNBC). Increased surface expression of transferrin receptor (TfR) is a downstream event of MYC upregulation and has been validated as a clinically relevant target for molecular imaging. Transferrin labeled with 89Zr has successfully identified MYC status in many cancer subtypes preclinically and been shown to predict response and changes in oncogene status via treatment with small-molecule inhibitors that target MYC and PI3K signaling pathways. We hypothesized that 89Zr-transferrin PET will noninvasively detect MYC and TfR and improve upon the current standard of 18F-FDG PET for MYC-overexpressing TNBC. Methods: In this study, 89Zr-transferrin and 18F-FDG imaging were compared in preclinical models of TNBC. TNBC cells (MDA-MB-157, MDA-MB-231, and Hs578T) were treated with bromodomain-containing protein 4 (BRD4) inhibitors JQ1 and OTX015 (0.5–1 mM). Cell proliferation, gene expression, and protein expression were assayed to explore the effects of these inhibitors on MYC and TfR. Results: Head-to-head comparison showed that 89Zr-transferrin targets TNBC tumors significantly better (P, 0.05–0.001) than 18F-FDG through PET imaging and biodistribution studies in MDA-MB-231 and MDA-MB-157 xenografts and a patient-derived xenograft model of TNBC. c-Myc and TfR gene expression was decreased upon treatment with BRD4 inhibitors and c-MYC small interfering RNA (P, 0.01–0.001 for responding cell lines), compared with vehicle treatment. MYC and TfR protein expression, along with receptor-mediated internalization of transferrin, was also significantly decreased upon drug treatment in MDA-MB-231 and MDA-MB-157 cells (P, 0.01–0.001). Conclusion: 89Zr-transferrin targets human TNBC primary tumors significantly better than 18F-FDG, as shown through PET imaging and biodistribution studies. 89Zr-transferrin is a useful tool to interrogate MYC via TfR-targeted PET imaging in TNBC. COPYRIGHT © 2018 by the Society of Nuclear Medicine and Molecular Imaging.
Keywords: controlled study; protein expression; human cell; nonhuman; comparative study; positron emission tomography; cell proliferation; mouse; animal tissue; gene overexpression; animal experiment; animal model; small interfering rna; in vivo study; antineoplastic activity; in vitro study; myc protein; fluorodeoxyglucose f 18; zirconium 89; oncogene myc; positron emission tomography (pet); transferrin; myc; triple negative breast cancer; transferrin receptor; human; female; priority journal; article; 4 (4 chlorophenyl) 2,3,9 trimethyl 6h thieno[3,2 f][1,2,4]triazolo[4,3 a][1,4]diazepine 6 acetic acid tert butyl ester; birabresib; 18f-fluorodeoxyglucose (18f-fdg); bromodomain-containing protein 4 (brd4); transferrin receptor (tfr); triple-negative breast cancer (tnbc); zirconium-89 (89zr); hs 578t cell line; mda-mb-157 cell line; mda-mb-231 cell line; tfr gene
Journal Title: Journal of Nuclear Medicine
Volume: 59
Issue: 1
ISSN: 0161-5505
Publisher: Society of Nuclear Medicine  
Date Published: 2018-01-01
Start Page: 51
End Page: 57
Language: English
DOI: 10.2967/jnumed.117.192286
PROVIDER: scopus
PMCID: PMC5750524
PUBMED: 28848040
Notes: Article -- Export Date: 1 February 2018 -- Source: Scopus
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MSK Authors
  1. Jason S Lewis
    243 Lewis
  2. Kimberly Joanna Edwards
    10 Edwards
  3. Kelly Elizabeth Henry
    5 Henry