EXTH-07. Enhancing 5-ALA Photodynamic Therapy with MEK Inhibition for Targeted Treatment of H3K27-Mutant Diffuse Midline Glioma
Year: 2025
Type: conference-abstract
Abstract: Diffuse midline gliomas (DMGs) are aggressive childhood brain tumors affecting midline central nervous system structures and are typically characterized by H3K27M mutations and MAPK pathway dysregulation. Due to poor tissue penetration associated with toxicity, conventional treatments offer limited benefit, prompting interest in local therapies. One emerging approach is 5-ALA photodynamic therapy (5-ALA-PDT), which uses a light-activated photosensitizer to generate ROS and selectively target tumor cells. Clinical trials in pediatric and adult high-grade gliomas have shown 5-ALA-PDT to be safe and feasible. Notably, it may act synergistically with MAPK-targeted therapies, especially given these tumors’ frequent MEK pathway alterations. We assessed the potential utility of combining 5-ALA-PDT and MEK inhibition as a novel treatment strategy for DMG to show that the anticancer activity of 5-ALA-PDT can be improved with MEK inhibitors trametinib (TRAM) (in vitro) and mirdametinib (in vivo). Significant inhibition of DMG cell survival and induction of apoptosis, combined with a significantly lower level of phospho-ERK, were observed upon 24 hours of combinatorial therapy (TRAM + 5ALA-PDT). The combination also reduces DMG cell invasion and migration by increasing intracellular levels of ROS. Immunofluorescence analysis showed decreased levels of PDGFRA and HSP90, reflecting suppression of tumor-promoting signaling pathways and the cellular stress response, respectively. Transcriptomic profiling indicated that these changes were driven by altered expression of tumor-associated genes. The combinatorial treatment was evaluated in two DMG mouse models: an immunocompetent genetically engineered model utilizing the RCAS/tv-a system, and a patient-derived xenograft. Enhanced cell death was observed in both models following treatment, along with increased neural stem differentiation, initiated T-cells infiltration and extended survival in the immunocompetent mice. These results demonstrate that combining 5-ALA-PDT with MEK inhibition can produce antitumor effects, offering proof of concept for the potential clinical application of this combination therapy.
Source: Neuro-Oncology
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W4416085437