Inhibition of Mitochondrial Bioenergetics and Hypoxia to Radiosensitize Diffuse Intrinsic Pontine Glioma.

Background: Diffuse Intrinsic Pontine Gliomas (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are brain tumors that primarily affect children. Radiotherapy is the standard of care but only provides temporary symptomatic relief due to radioresistance. While hypoxia is a major driver of radioresistance in other tumors, there is no definitive evidence that DIPGs are hypoxic.

Improving the synergistic combination of programmed death-1/programmed death ligand-1 blockade and radiotherapy by targeting the hypoxic tumour microenvironment.

Immune checkpoint inhibition with PD-1/PD-L1 blockade is a promising area in the field of anti-cancer therapy. Although clinical data have revealed success of PD-1/PD-L1 blockade as monotherapy or in combination with CTLA-4 or chemotherapy, the combination with radiotherapy could further boost anti-tumour immunity and enhance clinical outcomes due to the immunostimulatory effects of radiation. However, the synergistic combination of PD-1/PD-L1 blockade and radiotherapy can be challenged by the complex nature of the tumour microenvironment (TME), including the presence of tumour hypoxia.

Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas.

High-grade gliomas (HGGs), including glioblastoma and diffuse intrinsic pontine glioma, are amongst the most fatal brain tumors. These tumors are associated with a dismal prognosis with a median survival of less than 15 months. Radiotherapy has been the mainstay of treatment of HGGs for decades; however, pronounced radioresistance is the major obstacle towards the successful radiotherapy treatment.