Toward drug repurposing in epigenetics: Targeting histone modifications as a novel approach for a selective treatment for DMG
Year: 2025
Type: dissertation
Abstract: Diffuse Midline Glioma (DMG) is one of the most aggressive types of glial tumours, primarily affecting young children and representing the leading cause of brain tumour-related deaths in children. It most frequently occurs in children aged 5 to 10 but can present at any point during childhood. The prognosis for DMG is extremely poor, with a median survival time of 8 to 11 months, and only a small number of patients surviving beyond two years (Hargrave et al., 2006). The use of chemotherapy has shown no clinical benefit (Zhang et al., 2017b, Fangusaro, 2012) and conventional radiotherapy remains the only established treatment offering limited benefit. Unfortunately, radiotherapy is ineffective for the majority of patients, associated with poor outcomes (Fangusaro, 2012, Qaddoumi et al., 2009) and is palliative in nature. Therefore, there is an urgent need for innovative treatment approaches. In this study, I identified disulfiram as a drug that effectively kills DMG primary cells. Furthermore, I discovered that disulfiram induces a rapid decrease in histone acetylation—a key epigenetic feature that has previously been identified as a promising therapeutic target in DMG. I also demonstrated that disulfiram affects another potential drug target, MLL. Disulfiram has been used in the treatment of alcoholism for over sixty years and is thus already approved for clinical use. The aim of this study was to investigate the role of disulfiram in DMG and provide preclinical data supporting its efficacy. Disulfiram's significance lies in its potential for faster clinical translation compared to novel drug candidates (Zhang et al., 2020) as it has a well-established safety profile and evidence supporting its ability to cross the blood-brain barrier (Oskarsson, 1984). Consequently, translation of this research into clinical application could be accelerated.
Author: Gulacti, Ferah
Institution: University College London
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7113734004