Abstract
1149
Introduction: Targeted PET imaging of chemokine receptor 2 in head and neck cancer and progression
Objectives: The overall mortality rates of head and neck squamous cell carcinoma (HNSCC) have not significantly improved over the past several decades. A significant reason is the lack of tools, especially at the molecular level, to detect disease at early stages and to reliably assess presence of regional and/or distant metastasis. The expression of chemokine receptor 2 (CCR2) is increased in HNSCC. The goal of this study was to determine if changes in CCR2 expression with HNSCC progression could be imaged in patient derived xenografts (PDXs) tumor models with a novel targeted PET tracer, 64Cu-DOTA-ECL1i.
Methods: The CCR2 binding peptide, ECL1i, was conjugated to a DOTA chelator and radiolabeled with 64Cu. In vivo pharmacokinetic evaluation was performed in wild-type C57 mice. PET imaging was carried out in HNSCC PDX models at multiple time points during progression of the malignancy. The imaging specificity was confirmed by competitive receptor blocking studies. The expression of CCR2 in PDX tumors was characterized by immunohistochemistry (IHC). De-identified human HNSCC tissues were also used to confirm the up-regulation of CCR2 and test the binding of 64Cu-DOTA-ECL1i to this receptor.
Results: The integrity of DOTA-ECL1i was characterized with mass spectrometry. The high radiolabeling specific activity (1.04 mCi/nmol) led to tracer amount (10-100 pmol) administration for in vivo studies. Biodistribution of 64Cu-DOTA-ECL1i showed fast renal clearance with low accumulation in the liver. PET imaging in HNSCC PDX mice showed gradual increase in tumor uptake from 0.87 ± 0.14 %ID/g (n=8) at 9 weeks post tumor implantation to 1.70 ± 0.35 %ID/g (n=5) at 13 weeks. Competitive receptor blocking significantly decreased tumor uptake to 0.63 ± 0.08 %ID/g (n=3, p < 0.005), suggesting the targeting specificity. IHC of PDX tumors showed up-regulation of CCR2 in tumor cells, which was also confirmed in human HNSCC specimens. Autoradiography of 64Cu-DOTA-ECL1i in human HNSCC tumors demonstrated binding specificity and a similar profile to the immunostaining, indicating CCR2-mediated uptake.
Conclusions: CCR2 was identified as a biomarker to target HNSCC in both PDX models and human malignant tissues. 64Cu-DOTA-ECL1i demonstrated high CCR2 imaging sensitivity and specificity in PDX tumor models. Its binding capability to human tissue indicated the great potential for future clinical translation.