Proton Therapy and Src Family Kinase Inhibitor Combined Treatments on U87 Human Glioblastoma Multiforme Cell Line.

Francesco P Cammarata,Laura Maccari,Filippo Torrisi,Maurizio Botta,Valentina Bravatà,Giuseppe Ap Cirrone,Giusi I Forte,Gaetano Savoca,Silvia Schenone,Giacomo Cuttone,Giada Petringa,Pietro Pisciotta,Giorgio Russo,Anna L Fallacara,Marco Calvaruso,Rosalba Parenti,Luigi Minafra

doi:10.3390/ijms20194745

Abstract

Glioblastoma Multiforme (GBM) is the most common of malignant gliomas in adults with an exiguous life expectancy. Standard treatments are not curative and the resistance to both chemotherapy and conventional radiotherapy (RT) plans is the main cause of GBM care failures. Proton therapy (PT) shows a ballistic precision and a higher dose conformity than conventional RT. In this study we investigated the radiosensitive effects of a new targeted compound, SRC inhibitor, named Si306, in combination with PT on the U87 glioblastoma cell line. Clonogenic survival assay, dose modifying factor calculation and linear-quadratic model were performed to evaluate radiosensitizing effects mediated by combination of the Si306 with PT. Gene expression profiling by microarray was also conducted after PT treatments alone or combined, to identify gene signatures as biomarkers of response to treatments. Our results indicate that the Si306 compound exhibits a radiosensitizing action on the U87 cells causing a synergic cytotoxic effect with PT. In addition, microarray data confirm the SRC role as the main Si306 target and highlights new genes modulated by the combined action of Si306 and PT. We suggest, the Si306 as a new candidate to treat GBM in combination with PT, overcoming resistance to conventional treatments.

Highlights

Glioblastoma multiforme (GBM) is a central nervous system tumor classified as grade IV of high-grade malignant gliomas (HGG), according to the World Health Organization (WHO) guidelines [1]
To evaluate the radiosensitizing ability of Si306 compound, we investigated the combined effects of this molecule on U87 cells exposed to different proton doses (1, 2, 3, 4, 10, and 21 Gy)
We calculated the dose modifying factor (DMF), which represents the relative reduction of dose to be delivered following a combined treatment with Si306 to get the isoeffect of surviving fraction (SF) = 0.5 compared to radiation treatment without modification

Summary

Introduction

Glioblastoma multiforme (GBM) is a central nervous system tumor classified as grade IV of high-grade malignant gliomas (HGG), according to the World Health Organization (WHO) guidelines [1]. According to the ASTRO guidelines statements, the current standard care for GBM is surgical resection to the feasible extent, followed by conventional radiotherapy (RT) of 60 Gy delivered by fractions of 2 Gy, up to seven weeks. Chemotherapy is concurrent to RT with daily temozolomide (TMZ) administration [3,4,5]. These treatment modalities are not currently curative and the resistance to both chemotherapy and RT plans is the main cause of GBM care failures (the median survival time is 14.6 months) [6]. The dose release onto healthy brain tissue or surrounding organs at risk during irradiation may, substantially, contribute to late tissue toxicities, such as radionecrosis and neurocognitive dysfunction, because of their limited dose tolerance

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