Drug screening in the discovery of new therapeutic approaches for diffuse midline glioma

Abstract

Diffuse midline gliomas (DMGs) are highly aggressive brain tumours that occur most commonly in young children. The prognosis for patients with DMG is incredibly poor, with these tumours being almost universally fatal. Median survival is less than one year. To date, drugs have shown little efficacy in DMG, leaving palliative radiotherapy as the main treatment. Thus, new therapies are desperately needed. One approach to drug discovery for DMG is direct screening of patient-derived tumour cells with drug libraries to identify therapeutic vulnerabilities in these tumours. Here, we review the numerous studies performed in this area. We discuss the various models employed and the findings arising from these screens, which include large-scale screens of thousands of drugs, to smaller, targeted screens based on the known biology of DMG. These screens have revealed clear therapeutic vulnerabilities in DMG that include inhibition of histone deacetylases and the proteasome, amongst other targets. Few of these drugs, however, have ever demonstrated effect in mouse models of DMG or human trials. The challenge now is to determine whether these identified vulnerabilities can be more effectively targeted in combinational therapies and by enhancing drug delivery across the restrictive blood-brain barrier.