PP26. MULTIMODAL MOLECULAR IMAGING IN THE EVALUATION OF EARLY RESPONSE BIOMARKERS IN A GLIOMA MODEL
Authors: Dr Alessia Lo Dico, Dr Cecilia Diceglie, Dr Silvia Valtorta, Dr Isabella Raccagni, Dr Cristina Martelli, Dr Sara Belloli, Prof Giovanni Lucignani, Dr Letterio Politi, Prof Carlo Fiorini, Prof Rosa Maria Moresco, Dr luisa ottobrini
Journal: Neuro-Oncology (2017)

INTRODUCTION: Gliomas represent the most common adult neoplasm of the primary central nervous system (CNS) characterized by wide necrotic areas, high invasiveness, resistance to therapy and poor prognosis. Glioma is indeed refractory to conventional treatment combining surgery, radiotherapy and chemiotherapy (mostly Temozolomide, TMZ). Hypoxia is considered a major driving force for glioma progression inducing chemio- and radio-resistance, and sustaining tumor angiogenesis and invasiveness as well as proliferation with the hypoxia-mediated increase of HIF-1α activity. The presented research is part of the INSERT (INtegrated SPECT/MRI for Enhanced Stratification in Radio-chemo Therapy) project, a new collaborative research project founded by the European Seventh Research Framework Program (FP7) aimed at the development of a multi-modality imaging tool for concurrent SPECT and MRI studies to provide improved personalized radio-chemo therapies for brain tumors. Within this frame, the aim of the work, described herein, has been the identification of non-invasive theranostic biomarkers, involved in the regulation of tumor growth, and for the early assessment of tumor response to therapeutics using in vivo imaging strategies in an orthotopic mouse model of glioma. METHODS: Murine model was obtained by stereotaxic injection of human glioma cells (U251-HRE expressing Luciferase reporter gene under the control of multiple copies of hypoxia responsive element). Mice were treated with TMZ 400 mg/kg o.s 21 days after cell injection. Tumor growth was monitored in vivo with MRI (7 Tesla Bruker scanner) and Optical imaging (BLI and FLI, IVIS SPECTRUM/CT instrument), before and after treatment (0, 2 and 7 days). Moreover, ex vivo preliminary uptake studies were performed by autoradiography with [99mTc]MIBI. For MRI examinations were used different sequences such as: EPI-DTI (Diffusion Tensor), Turbo Spin Echo T2, Rare T1 Map, Dynamic Contrast Enhancement (DCE) Dynamic Susceptibility Contrast (DSC) and T1 post-contrast. RESULTS: TMZ treatment, beyond the already published reduction of HIF-1 activity, induced a reduction of tumor volume reported both by MRI and autoradiography one week after treatment. Treatment efficacy induced also variation of MRI detectable phenomena, such as diffusion and contrast enhancement (DWI and DCE MRI sequences). [99mTc]MIBI uptake resulted significantly lowered after TMZ treatment allowing the identification of responsive tumors. These data correlate with those already obtained by BLI and FLI. CONCLUSIONS: This study suggests that, in the U251-HRE orthotopic murine model, the responsiveness to TMZ treatment induced a pattern of changes probably involved with HIF-1 activity. These changes can be monitored by multiparametric analysis, and will be assessed using the newly hybrid imaging system proposed by INSERT project, allowing the validation of the new theranostic biomarkers of early tumor response to treatment. ACKNOWLEDGMENT: This work was supported by the FP7 INSERT project (HEALTH-2012-INNOVATION-1, GA305311).