Metabolic imaging using hyperpolarized pyruvate-lactate exchange assesses response or resistance to the EGFR inhibitor cetuximab in patient-derived HNSCC xenografts.
(2020) Clinical cancer research — Vol. 15, n° 26(8), p. 1932-1943 (2020)
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- (en) PURPOSE: Optimal head and neck squamous cell carcinoma (HNSCC) patient selection for Anti-EGFR-based therapy remains an unmet need since only a minority of patients derive long-term benefit from cetuximab treatment. We assessed the ability of state-of-the-art noninvasive in vivo metabolic imaging to probe metabolic shift in cetuximab-sensitive and -resistant HNSCC patient-derived tumor xenografts (PDTXs). EXPERIMENTAL DESIGN: Three models selected based on their known sensitivity to cetuximab in patients (cetuximab-sensitive or acquired-resistant HNC007 PDTXs, cetuximab-naïve UCLHN4 PDTXs, and cetuximab-resistant HNC010 PDTXs) were inoculated in athymic nude mice. RESULTS: Cetuximab induced tumor size stabilization in mice for 4 weeks in cetuximab-sensitive and -naïve models treated with weekly injections (30 mg/kg) of cetuximab. Hyperpolarized 13C-pyruvate-13C-lactate exchange was significantly decreased in vivo in cetuximab-sensitive xenograft models 8 days after treatment initiation, whereas it was not modified in cetuximab-resistant xenografts. Ex vivo analysis of sensitive tumors resected at day 8 after treatment highlighted specific metabolic changes, likely to participate in the decrease in the lactate to pyruvate ratio in vivo. Diffusion MRI showed a decrease in tumor cellularity in the HNC007-sensitive tumors, but failed to show sensitivity to cetuximab in the UCLHN4 model. CONCLUSIONS: This study constitutes the first in vivo demonstration of cetuximab-induced metabolic changes in cetuximab-sensitive HNSCC PDTXs that were not present in resistant tumors. Using metabolic imaging, we were able to identify hyperpolarized 13C-pyruvate as a potential marker for response and resistance to the EGFR inhibitor in HNSCC.
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Mignion, L., Acciardo, S., Gourgue, F., Joudiou, N., Caignet, X., Goebbels, R.-M., Corbet, C., Feron, O., Bouzin, C., Cani, P., Machiels, J.-P., Schmitz, S., & Jordan, B. (2020). Metabolic imaging using hyperpolarized pyruvate-lactate exchange assesses response or resistance to the EGFR inhibitor cetuximab in patient-derived HNSCC xenografts. Clinical cancer research, 15(26(8)), 1932-1943. https://doi.org/10.1158/1078-0432.CCR-19-1369 (Original work published 2020)