Enhancing intensity of tumor-specific fluorescence by MEK inhibition in brain tumor models

Abstract

Fluorescence guided surgery using 5-aminolevulinic acid (5-ALA FGS), a technique widely used to resect brain tumors, relies on fluorescence signals from Protoporphyrin IX (PpIX) accumulated in cancer cells to identify and resect tumor tissue. Despite its clinical success, a major issue of 5-ALA FGS is the insufficient accumulation of PpIX in tumors, posing challenges to the surgeons to delineate tumor ends. Our previous research showed that MEK inhibition increases PpIX accumulation in cancer cells but not in normal cells. In this study, we aimed to screen different MEK inhibitors for their efficacy in promoting 5-ALA mediated PpIX accumulation in human brain cancer cell lines in vitro. Furthermore, we sought to develop an animal model of brain cancer to evaluate the efficacy of screened MEK inhibitors in enhancing tumor visualization in vivo. By conducting in vitro fluorescence measurements, we found that MEK inhibitors Trametinib and Selumetinib were most effective in promoting PpIX accumulation in cancer cell lines. For its consistent robust effect in vitro, Selumetinib was selected for evaluation in in vivo experiments. We successfully developed a mice brain tumor model in Balb/c mice by allografting mammary cancer 4T1 cells into the brain's right hemisphere. Preliminary 2-Photon imaging results show a substantial increase in PpIX fluorescence in mice treated with Selumetinib and 5-ALA compared to mice with vehicle (DMSO/saline) and 5-ALA treatment. These results indicate the potential use of MEK inhibitor treatment to promote PpIX fluorescence in brain tumors for improved 5-ALA FGS in clinical settings.