EXTH-58. USING MEK INHIBITOR TO ENHANCEMENT 5-ALA MEDIATED SONODYNAMIC THERAPEUTIC EFFECT: A PRECLINICAL STUDY

Abstract

Abstract The potential of sonodynamic therapy (SDT) using sono-sensitive molecules such as 5-aminolevulinic acid to treat brain tumor is highly noted for glioma treatment. However, the accumulation of 5-ALA in glioma cells is limited by the heterogeneous cell types of GBM. MEK inhibitor is known to be effective on enhance the accumulation of 5-ALA in glioma cells, therefore, we aim to study the effect of MEK inhibition on sonodynamic therapy. MEK inhibitor trametinib were systemically administered to animals bearing subcutaneous tumor xenograft 24 hours prior to treatment. Subsequently, the effects of 5-ALA-mediated sonodynamic therapy were determined by measuring the volume of tumor xenografts and the bodyweights animals. Glioma cells and tissue samples were collected, and the effect on MEK signaling pathway were evaluated by immunohistochemistry/PCR/Western blotting. For tumor growth data, comparison across multiple groups was performed with repeated measures two-way analysis of variance (ANOVA). Animals were divided into 5 groups: control, focused ultrasound (0.35 MPa.duty10%.10min), trametinib (1mg/kg), 5ALA (180mg/Kg) +FUS, trametinib(1mg/Kg)+5ALA(180mg/Kg) +FUS (n = 5 for each group). Following treatment, tumor growth was monitored by digital caliper twice a week. As compared with control group, the tumor size of trametinib+5ALA+FUS group is significantly less than control group (p = 0.0085, 0.0001 and 0.0255 at day 4, 7 and 11). No significant difference was observed in other groups verse control. The daily mice body weight records revealed no significant change, demonstrated no major toxicity was induced by the MEK inhibitor/5-ALA/sonodynamic combination treatment. Our study demonstrates that suppression of MEK pathway by MEK inhibitor trametinib significantly increase the accumulation of PpIX. In tumor animal models, mice pretreated with MEK inhibitor presented favorable response to 5-ALA mediated sonodynamic therapy. Our finding may suggest a new strategy to enhance the effect of sonodynamic therapy.