Abstract Diffuse intrinsic pontine glioma (DIPG) is an inoperable pediatric brain cancer with median survival of 7-11 months. Radiotherapy is the current standard of care, without chemotherapeutic survival benefit. Sonodynamic therapy (SDT) for DIPG utilizes MR-guided low-intensity focused ultrasound and 5-aminolevulinic acid to induce mitochondrial dysfunction and tumor apoptosis. Herein, we describe the systemic cytokine and metabolomic profile observed in a DIPG patient treated with SDT. Furthermore, we evaluate treatment effect in the post-treatment tissue obtained post-mortem. We hypothesized that SDT induces systemic metabolic and pro-inflammatory changes that can be characterized in plasma and urine. Post-treatment tissue evaluation will demonstrate the direct treatments effects of SDT. Blood and urine were obtained at time intervals before, during, and after SDT. Longitudinal plasma specimens were processed by Meso-Scale-Discovery (MSD) to evaluate plasma cytokine and immune activation. Plasma metabolomics and urine proteomics were analyzed. Postmortem tumor and adjacent healthy brain tissue underwent electron microscopy (mitochondrial changes). MSD demonstrated elevation in pro-inflammatory cytokines (IL-6,5,12,TNF-a), which returned to baseline 3 weeks after treatment, and anti-inflammatory IL-10, which increased after 2 weeks. Plasma alteration in several essential, conditional-essential, and non-essential amino acids; including increased (6 FC) beta-alanine and hydroxylysine was observed post-SDT. Urine proteomic analysis was notable for elevated markers involved in mitochondria, apoptosis, humoral immunity, heme metabolism, and oxidation. Ruptured mitochondrial outer membranes were increased in SDT treated tumor tissue compared to control assessed by electron microscopy. In this patient with DIPG, we observed a pro-inflammatory response after SDT, characterized by elevation of pro-inflammatory cytokines that return to baseline 2 weeks after treatment. Further characterization of the response is required to understand its significance and future utility as a biomarker of response. Spatial transcriptomics and whole genome sequencing analyses are currently underway and will aid help elucidate the mechanisms of action of SDT in DIPG.
Keating et al. (Fri,) studied this question.
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