Abstract
The epidermal growth factor receptor (EGFR) is one of the most comprehensively studied molecular targets in head and neck squamous cell carcinoma (HNSCC). However, inherent and acquired resistance are serious problems and are responsible for limited clinical efficacy and tumor recurrence. In this study, we evaluated the feasibility of immuno-positron emission tomography (PET) imaging and radioimmunotherapy (RIT) with 64Cu-/177Lu-PCTA-cetuximab in cetuximab-resistant SNU-1066 HNSCC xenografted model. The cellular uptake of 64Cu/177Lu-3,6,9,15-tetraazabicyclo[9.3.1]-pentadeca-1(15),11,13-triene-3,6,9,-triacetic acid (PCTA)-cetuximab showed good correlation with western blot and flow cytometry analysis in EGFR expression level of various HNSCC cells. 177Lu-PCTA-cetuximab selectively killed cetuximab-resistant SNU-1066 cells in vitro. 64Cu-/177Lu-PCTA-cetuximab specifically accumulated in SNU-1066 tumor and those uptakes were peaked at 48 h and 7 day, respectively in biodistribution, PET and single-photon emission computed tomography/computed tomography (SPECT/CT) imaging. RIT with single dose of 177Lu-PCTA-cetuximab exhibited significant tumor regression and markedly reduced 2-[18F]fluoro-2-deoxy-D-glucose (18F-FDG) uptake, compared to other groups. Proliferation index were dramatically decreased and apoptotic index increased in RIT group. These results suggest that a diagnostic and therapeutic convergence radiopharmaceutical, 64Cu-/177Lu-PCTA-cetuximab has the potential of target selection using immuno-PET imaging and targeted therapy by RIT in EGFR expressing cetuximab-resistant HNSCC tumors.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer, with an annual worldwide incidence rate of more than 600,000 [1]
We aimed to evaluate the feasibility of immuno-positron emission tomography (PET) imaging-based radioimmunotherapy and the therapeutic efficacy with the diagnostic and therapeutic convergence radiopharmaceutical, 64Cu-/177Lu-cetuximab, in SNU1066 HNSCC xenograft model, which was resistant to immunotherapy with cetuximab
Epidermal growth factor receptor (EGFR) expression level and cytotoxicity by cetuximab in HNSCC cell lines The relative expression levels of EGFR in four HNSCC cell lines were determined by western blot (Figure 1a) and flow cytometry (Figure 1b)
Summary
Head and neck squamous cell carcinoma (HNSCC) is the seventh most common cancer, with an annual worldwide incidence rate of more than 600,000 [1]. In only 50% of HNSCC patients, the current conventional treatment strategies including surgery, chemotherapy, and radiation, are effective. The concomitant chemo-radiation strategy has been used for locally advanced resectable cancers, there seems to be no survival benefit compared with other treatments [2, 3]. In HNSCC patients with unresectable advanced disease, the combined therapy only achieved suboptimal disease control with a 5-year survival rate of < 10% [4]. As our understanding of the molecular biology of HNSCC continues to improve, this may provide the opportunity to develop molecular targeted therapy for HNSCC treatment. EGFR overexpression is associated with poor prognosis, increased tumor growth, metastasis, and resistance to chemotherapy and radiation therapy [8]. Small-molecule tyrosine kinase inhibitors and monoclonal antibodies against EGFR, cetuximab and panitumumab, etc, have shown limited efficacy in head and neck cancer [9,10,11,12]
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