Radiotherapy is the only standard of care for H3K27M mutant diffuse midline glioma. Unfortunately, following initial response tumors recur. Experimental therapeutics can synergize with radiotherapy to produce a greater therapeutic effect than either agent alone, a concept known as 'radiosensitization'. Our team has pioneered this concept both in the laboratory and clinic including in successful bench-to-bedside translational studies in patients with brain tumors. In addition, our team recently demonstrated that an experimental therapy known as ONC201 has promising efficacy in H3K27M diffuse midline glioma patients. The potential for ONC201 or its next generation derivative ONC206 to synergize with radiotherapy to selectively radiosensitize H3K27M mutant diffuse midline glioma has not been investigated. In this application, we will develop a maximally effective therapeutic combination of ONC201 or ONC201 with concurrent radiotherapy that we expect will be immediately informative to clinical trials in H3K27M diffuse midline glioma patients.