Abstract Diffuse intrinsic pontine glioma (DIPG) arises within the pons of the brainstem in children ages 5 – 7 years with a median survival of one year. DIPGs are surgically inaccessible and radiation therapy (XRT) provides only transient benefit, with death ensuing from relentless local tumour infiltration. DIPGs are now the leading cause of brain tumour deaths in children with a societal cancer burden in years of life lost (YLL) of more than 67 per individual. Whole-genome and -exome sequencing indicate that ~80% of DIPGs harbor histone H3 mutations leading to a Lys27Met (K27M) substitution, causing globally reduced H3K27 methylation. Additional recurrent drivers include TP53 mutations (~80%), PDGFRA alterations (~40%), and ACVR1 mutations (~25%), each contributing to tumorigenesis through pathways like aberrant receptor tyrosine kinase signaling (PI3K/AKT/mTOR, Ras/Raf/MEK/ERK). We developed a novel approach to experimental DIPG using magnetic resonance guided focused ultrasound (MRgFUS) in rodents to deliver non-penetrant chemotherapy across the blood brain barrier into DIPG models. When doxorubicin was administered in these models, a 4-fold increase in concentration of drug was observed. DIPG tumours demonstrated a reduced proliferation by Ki-67 immunohistochemistry and size by bioluminescence. These results led to a first in child Phase I safety and feasibility clinical trial for DIPG. An update on patients treated in this clinical trial will be presented. In addition, we will describe our current experimental approach to harness the immune system as a combinatorial strategy with targeted chemotherapy to reduce the growth rate and improve survival in this devastating paediatric brain tumour.
Rutka et al. (2025) studied this question.