Multi-modal molecular imaging of anti-angiogenic treatment strategies of experimental gliomas

Background: Glioblastomas are highly vascularized tumors. Hence, anti-angiogenic treatments are an attractive option. However, they are limited by the potential evolution of the tumor cells towards infiltrative, angiogenic independent cells, leading to recurrence of the cancer. Development of imaging methods to non-invasively characterize the tumor vasculature in terms of vessel size, density and neo-angiogenesis and the tumor proliferation is essential to assess the effect of anti-angiogenic treatment.

Aim: The goal of our study was to describe changes in tumor vasculature and proliferation upon Bevacizumab treatment (anti-VEGF neutralizing antibody) using positron emission tomography imaging (PET) and magnetic resonance imaging (MRI).

Methods: Nude rats (n=12) were intracranially implanted with human glioblastoma biopsy samples. Three weeks after tumor implantation, [C-11]methionine (MET) and [F-18]fluorothymidine (FLT) PET as well as diffusion weighted imaging (DWI) and steady state contrast enhancement (SSCE) MRI were performed. Half of the rats were then treated with weekly injection of 10mg/kg of Bevacizumab for 3 weeks. Imaging was performed again after treatment. Tumors were then analyzed by immuno-histochemistry.

Results: Three weeks after implantation tumors could be observed on the T2*-weighted MR images but were barely visible on the PET scans. MRI analyses showed an increase of the vessel density and the cerebral blood volume. Three weeks later treated and non-treated rats showed an increase of FLT and MET uptake. Accumulation of both tracers was however less intense for the treated group compared to the non-treated group (MET, p=0.035; FLT, p=0.190). In both groups total blood volume and vessel size were increased at week 6 compared to week 3, whereas vessel density was decreased. Microvessel blood volume was decreased in treated rats compared to the non-treated rats (p=0.013), whereas mean vessels size was increased (p<0.01). Immuno-histochemical analyses confirmed imaging data.

Conclusion: Bevacizumab treatment failed to prevent formation of dilated vessels but development of new small vessels was decreased. Good correlation was observed between MET uptake, calculation of vessel size and density using the MRI scans and histological observations. These data indicate that multi-modal imaging by PET and MRI reveals important information on anti-angiogenic treatment strategies in gliomas.

Supported by: BMBF, MoBiMed