Does Imaging αvβ3 Integrin Expression with PET Detect Changes in Angiogenesis During Bevacizumab Therapy?

In recent years, there has been a growing interest in molecular imaging markers of tumor-induced angiogenesis. Several radiolabeled RGD (arginine, glycine, aspartate) peptides have been developed for PET imaging of alpha(v)beta(3) integrins in the tumor vasculature, but there are only limited data on how angiogenesis inhibitors affect the tumor uptake of these peptides. Methods: Changes in Ga-68-NODAGA-c(RGDfK) peptide uptake were measured using PET during bevacizumab therapy of 2 alpha(v)beta(3)-negative squamous cell carcinoma cell lines (A-431 and FaDu) that induce alpha(v)beta(3)-positive neovasculature when transplanted into nude mice. Tumor uptake of Ga-68-NODAGA-c(RGDfK) was correlated to microvascular density, vascular morphology, and permeability as well as alpha(v)beta(3) integrin expression. Results: Bevacizumab significantly inhibited growth of A-431 tumors and caused a significant reduction in microvascular density and alpha(v)beta(3) integrin expression within 7 d after start of therapy. Bevacizumab also caused a normalization of blood vessel morphology and decreased tumor necrosis. However, Ga-68-NODAGA-c(RGDfK) uptake was significantly increased at day 7 of therapy and did not decrease until after 3 wk of treatment. In Fadu xenografts, bevacizumab therapy caused only a minor inhibition of tumor growth and minor changes in Ga-68-NODAGA-c(RGDfK) uptake. Conclusion: Uptake of radiolabeled RGD peptides is not necessarily decreased by effective antiangiogenic therapy. Early in the course of therapy a decrease in the expression of alpha(v)beta(3) integrins may not be reflected by a decrease in the uptake of RGD peptides.