Influence of glycolytic phenotype on anti-angiogenic therapy response in ovarian cancer xenograft models evaluated by PET imaging

Introduction: Use of anti-angiogenic therapy is increasing in many types of cancer but therapeutic response is heterogeneous. Moreover, predictive biomarkers for patients stratification are currently lacking. Previously, levels of "glucose addiction" modulated pathologic response of tumor xenografts to VEGF neutralization. Here we investigated, short- and long-term response to anti-angiogenic therapy by evaluating cell proliferation and regional hypoxia changes by in vivo [18F]FLT and [18F]FAZA PET imaging. Methods: Mice were injected with 4x105 poorly glycolytic IGROV-1 (n=20) or 3x105 highly glycolytic OC316 cells (n=20) mixed with liquid Matrigel. Xenografts mice were randomized into two groups: control (n=10) and treated (n=10). Bevacizumab (Avastin; i.p. 5 mg/kg) administration started when tumours reached 90-100 mm3 volume and lasted for 4 weeks. Animals underwent PET with [18F]FLT and [18F]FAZA at the baseline and 7 and 28 days from the beginning of therapy. Quantification analysis was performed with pmod 2.7 software and max radiotracers uptake values (SUVmax), tumor to background ratio and metabolic volumes were obtained. Finally, histological and immunohistochemical analysis were performed. Results: At 7 days, volume of OC316 treated tumours was smaller than that of controls but there were no differences in radiotracers uptake. Moreover, treated tumours became necrotic and rapidly resistant to anti-VEGF therapy. In contrast, in IGROV-1 xenografts we observed an early but transient reduction in [18F]FLT uptake (7 d; p<0.05) and a long-term cytostatic effect as revealed by the lack of tumour volume increase up to 28 days. However, despite their small size, tumours treated with bevacizumab were composed by highly proliferative and hypoxic cells as indicated by PET imaging. Finally, at the end of treatment IGROV-1 tumours showed large necrotic areas as OC-316 treated tumours. Conclusions: Bevacizumab arrests growth of poorly glycolytic tumours although it selects a more aggressive phenotype, as indicated by [18F]FLT and [18F]FAZA PET images. Finally, the lack of reduction in [18F]FLT uptake at the end of treatment might be predictive of anti-VEGF resistance associated with the highly glycolytic phenotype. The evaluation of the relapse of disease in IGROV-1 under suspension or maintenance therapy is under investigation. Acknowledgements: Research supported by AIRC Project Molecular and Cellular Imaging of Cancer and by PIO Project PET Molecular Imaging.