Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways

UNLABELLED Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293

Mediterranean Policies from Above and Below

International audienceThe Union for the Mediterranean (UfM) has brought the Mediterranean region back to the political agenda. This volume provides, for the first time, a comprehensive overview and comparative analysis of Mediterranean policies of governmental and non-governmental actors, from above and below. It includes case studies on the Mediterranean policies of numerous southern and eastern Mediterranean States, various EU Member States, and the EU itself. The case studies explain how and why these States, all participating in the Euro-Mediterranean Partnership, now UfM, are according a particular importance to the Mediterranean region within their foreign policies. The case studies on civil society groups or social movements such as informal or formal human rights networks, women’s networks, migrant networks, or entrepreneurs provide a broad overview of the multifaceted and dynamic civil society landscape in the Euro-Mediterranean region. Bringing together well-known scholars and experts from Europe, North Africa, and the Middle East, the book explores the questions of why and how the forms, the intensity, and the efficiency of interactions and articulations between the above and the below are developing within Mediterranean policies

Mediterranean Policies from Above and Below

International audienceThe Union for the Mediterranean (UfM) has brought the Mediterranean region back to the political agenda. This volume provides, for the first time, a comprehensive overview and comparative analysis of Mediterranean policies of governmental and non-governmental actors, from above and below. It includes case studies on the Mediterranean policies of numerous southern and eastern Mediterranean States, various EU Member States, and the EU itself. The case studies explain how and why these States, all participating in the Euro-Mediterranean Partnership, now UfM, are according a particular importance to the Mediterranean region within their foreign policies. The case studies on civil society groups or social movements such as informal or formal human rights networks, women’s networks, migrant networks, or entrepreneurs provide a broad overview of the multifaceted and dynamic civil society landscape in the Euro-Mediterranean region. Bringing together well-known scholars and experts from Europe, North Africa, and the Middle East, the book explores the questions of why and how the forms, the intensity, and the efficiency of interactions and articulations between the above and the below are developing within Mediterranean policies