Journal
JOURNAL OF NUCLEAR MEDICINE
Volume 59, Issue 1, Pages 51-57Publisher
SOC NUCLEAR MEDICINE INC
DOI: 10.2967/jnumed.117.192286
Keywords
triple-negative breast cancer (TNBC); positron emission tomography (PET); zirconium-89 (Zr-89); F-18-fluorodeoxyglucose F-18-FDG); MYC; transferrin receptor (TfR); bromodomain-containing protein 4 (BRD4)
Funding
- National Institutes of Health [R01CA176671, R00CA172695, P30 CA008748]
- MSKCC Center for Molecular Imaging and Nanotechnology Tow Fellowship
- David H. Koch Young Investigator Award from the Prostate Cancer Foundation
- Department of Defense Idea Development Award [PC140107]
- UCSF Academic Senate
- GE Healthcare
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The current standard for breast PET imaging is F-18-FDG. The heterogeneity of F-18-FDG uptake in breast cancer limits its utility, varying greatly among receptor status, histopathologic subtypes, and proliferation markers. F-18-FDG PET often exhibits nonspecific internalization and low specificity and sensitivity, especially with tumors smaller than 1 cm(3). 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 Zr-89 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 Zr-89-transferrin PET will noninvasively detect MYC and TfR and improve upon the current standard of F-18-FDG PET for MYC-over-expressing TNBC. Methods: In this study, Zr-89-transferrin and (18)-FFDG 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 mu M). 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 Zr-89-transferrin targets TNBC tumors significantly better (P < 0.05-0.001) than F-18-FDG through PET imaging and biodistribution studies in MDA-MB-231 and MDA-MB-157 xeno-grafts 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: Zr-89-transferrin targets human TNBC primary tumors significantly better than F-18-FDG, as shown through PET imaging and biodistribution studies. Zr-89-transferrin is a useful tool to interrogate MYC via TfR-targeted PET imaging in TNBC.
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