Dr. Nicole Shonka of Nebraska Medicine and Dr. Robert Chong of UCLA Health discuss the evolving care of high-grade glioma in adults and children, focusing on the distinction between glioblastoma, isocitrate dehydrogenase (IDH) wild-type, and diffuse midline glioma (DMG), H3 K27-altered, under the 2021 World Health Organization (WHO) classification. They review imaging clues, essential molecular workup, and the August 2025 accelerated US Food and Dr.ug Administration (FDA) approval of dordaviprone (Modeyso) for recurrent H3 K27M-mutant DMG in patients 1 year of age and older. Discussion covers dordaviprone’s mechanism, the 22% overall response rate (ORR) from a 5-trial integrated analysis, weekly oral dosing and safety, sequencing at progression, response assessment with Response Assessment in Neuro-Oncology (RANO) 2.0, and patient communication.
In this opening episode, Dr. Shonka and Dr. Chong frame the conversation around two diseases that share the name glioma but differ fundamentally in biology, demographics, and treatment.
n this episode, Dr. Chong sets up the clinical reality that patients usually present with imaging before tissue and asks Dr. Shonka how MRI findings should shape suspicion for DMG.
In this episode, Dr. Shonka asks Dr. Chong what molecular testing he considers essential for every newly diagnosed glioma, and how to ensure H3 K27M status is captured in midline tumors where tissue is limited.
In this episode, Dr. Chong asks Dr. Shonka to explain what dordaviprone is and how it works. Dr. Shonka describes dordaviprone (previously known as ONC201) as a blood–brain-barrier–penetrant, first-in-class imipridone with two mechanisms: antagonism of the dopamine D2 receptor (DR.D2), which activates the integrated stress response through the ATF4/CHOP pathway and drives apoptosis; and agonism of the mitochondrial protease ClpP, which disrupts oxidative phosphorylation and the electron transport chain.
In this episode, Dr. Chong asks Dr. Shonka to describe how she frames the dordaviprone regimen with patients and how its administration compares with other glioma therapies. Dr. Shonka highlights the practical advantages: once-weekly oral dosing on an empty stomach, no injections, and capsules that can be opened and mixed with liquid for patients with swallowing difficulties.
In this episode, Dr. Chong asks Dr. Shonka which patient profiles make her more or less likely to use dordaviprone.
In this episode, Dr. Shonka asks Dr. Chong how he sequences therapy across the disease course. For newly diagnosed DMG, both rely on radiation followed by temozolomide — acknowledging that benefit is limited — and then move to dordaviprone at first recurrence for H3 K27M-mutant disease.
In this final episode, Dr. Chong asks Dr. Shonka how she approaches the initial conversation with a newly diagnosed patient — particularly a young adult or AYA patient.
