Metabolic Imaging Allows Early Prediction of Response to Vandetanib

Abstract

The RET (rearranged-during-transfection protein) protooncogene triggers multiple intracellular signaling cascades regulating cell cycle progression and cellular metabolism. We therefore hypothesized that metabolic imaging could allow noninvasive detection of response to the RET inhibitor vandetanib in vivo. Methods: The effects of vandetanib treatment on the full-genome expression and the metabolic profile were analyzed in the human medullary thyroid cancer cell line TT. In vitro, transcriptional changes of pathways regulating cell cycle progression and glucose, dopa, and thymidine metabolism were correlated to the results of cell cycle analysis and the uptake of ³H-deoxyglucose, ³H-3,4-dihydroxy-l-phenylalanine, and ³H-thymidine under vandetanib treatment. In vivo, the tumor metabolism under vandetanib was monitored by small-animal PET of tumor-bearing mice. Results: Vandetanib treatment resulted in the transcriptional downregulation of various effector pathways with consecutive downregulation of cyclin expression and a G₀/G₁ arrest. In vitro, vandetanib treatment resulted in the decreased expression of genes regulating glucose, 3,4-dihydroxy-l-phenylalanine, and thymidine metabolism, with a subsequent reduction in the functional activity of the corresponding pathways. In vivo, metabolic imaging with PET was able to assess changes in the tumoral glucose metabolism profile as early as 3 d after initiation of vandetanib treatment. Conclusion: We describe a metabolic imaging approach for the noninvasive detection of successful vandetanib treatment. Our results suggest that PET may be useful for identifying patients who respond to vandetanib early in the course of treatment.