Affibody-based PET imaging to guide EGFR-targeted cancer therapy in head and neck squamous cell cancer models.
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In head and neck squamous cell carcinoma (HNSCC), the human epidermal growth factor receptor 1 (EGFR) is the dominant signaling molecule among all members of the family. So far, cetuximab is the only approved anti-EGFR mAb used for the treatment of HNSCC, but despite the benefits of adding it to standard treatment regimens, attempts to define a predictive biomarker to stratify patients for cetuximab treatment have been unsuccessful. We hypothesized that imaging with EGFR-specific radioligands may facilitate non-invasive measurement of EGFR expression across the entire tumor burden and also allow for dynamic monitoring of cetuximab-mediated changes in receptor expression. Methods: EGFR-specific Affibody molecule (ZEGFR:03115) was radiolabeled with zirconium-89 (89Zr) and fluorine-18 (18F). The radioligands were characterized in vitro and in mice bearing subcutaneous tumors with varying levels of EGFR expression. The protein dose for imaging studies was assessed by injecting 89Zr-DFO-ZEGFR:03115 (2.4-3.6 MBq, 2 µg) either together with or 30 mins after increasing amounts of unlabeled ZEGFR:03115 (1, 5, 10, 15 and 20 µg). PET images were acquired at 3, 24 and 48 h post-injection and the image quantification data were correlated with the biodistribution results. The EGFR expression and biodistribution of the tracer were assessed ex vivo by immunohistochemistry, Western blot and autoradiography. To downregulate the EGFR level, treatment with cetuximab was performed and 18F-AlF-NOTA-ZEGFR:03115 (12 µg, 1.5-2 MBq/mouse) used to monitor receptor changes. Results: In vivo studies demonstrated that co-injecting 10 µg of non-labeled molecules with 89Zr-DFO-ZEGFR:03115 allows for clear tumor visualization 3 h post-injection. The radioconjugate tumor accumulation was EGFR-specific and PET imaging data showed a clear differentiation between xenografts with varying EGFR expression levels. A strong correlation was observed between PET analysis, ex vivo estimates of tracer concentration and receptor expression in tumor tissues. Additionally, 18F-AlF-NOTA-ZEGFR:03115 could measure receptor downregulation in response to EGFR inhibition. Conclusion: ZEGFR03115-based radioconjugates can assess different levels of EGFR level in vivo and measure receptor expression changes in response to cetuximab, indicating a potential for assessment of adequate treatment dosing with anti-EGFR antibodies.
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Oncology: Head and neck
Preclinical Molecular Imaging
Translational Molecular Imaging
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J Nucl Med, 2018