Abstract
In head and neck squamous cell cancer, 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 monoclonal antibody used for the treatment of head and neck squamous cell cancer, 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 noninvasive measurement of EGFR expression across the entire tumor burden and allow for dynamic monitoring of cetuximab-mediated changes in receptor expression. Methods: EGFR-specific Affibody molecule (ZEGFR:03115) was radiolabeled with 89Zr and 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-deferoxamine-ZEGFR:03115 (2.4–3.6 MBq, 2 μg) either together with or 30 min after increasing amounts of unlabeled ZEGFR:03115 (1, 5, 10, 15, and 20 μg). PET images were acquired at 3, 24, and 48 h after 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-aluminium fluoride-NOTA-ZEGFR:03115 (12 μg, 1.5–2 MBq/mouse) was used to monitor receptor changes. Results: In vivo studies demonstrated that coinjecting 10 μg of nonlabeled molecules with 89Zr-deferoxamine-ZEGFR:03115 allows for clear tumor visualization 3 h after 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-aluminium fluoride-NOTA-ZEGFR:03115 could measure receptor downregulation in response to EGFR inhibition. Conclusion: ZEGFR:03115-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.
Highlights
Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer; its treatment consists of surgery or radiotherapy, with or without concurrent chemotherapy or targeted therapy [1]
To demonstrate that ZEGFR:03115 targets epidermal growth factor receptor 1 (EGFR), HN5 cells were incubated with ZEGFR:03115-Dylight633 and the cell-associated fluorescence was visualized by confocal microscopy
Despite evidence demonstrating an important prognostic role for EGFR in head and neck squamous cell cancer (HNSCC), receptor expression has not been predictive of response to EGFR-targeted therapy
Summary
Head and neck squamous cell cancer (HNSCC) is the sixth most common cancer; its treatment consists of surgery or radiotherapy, with or without concurrent chemotherapy or targeted therapy [1]. An 89Zr-labeled conjugate was used to assess tumor-to-organ ratios at different time points and a 18F-labeled analog to measure the response to cetuximab treatment in vivo These data support the hypothesis that a targeted PET agent can quantify EGFR expression. It is important to consider the context in which EGFR has been assessed in previous clinical studies, in order to understand the limitations of the methodologies used At this moment, no serum biomarker has been identified that can consistently classify an EGFR-positive subgroup of patients for targeted therapies; in most clinical trials, EGFR expression has been measured via immunohistochemical staining before the initiation of therapy at a single, static time point, and on a relatively small tissue sample [10]. We hypothesized that incorporating imaging with EGFR-specific radioligands into routine clinical practice may facilitate a noninvasive, real-time measurement of EGFR expression across the patient’s entire tumor burden and allow for dynamic monitoring of cetuximab-mediated receptor downregulation, providing a marker for adequate treatment dosing
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