(Epi)genetically Re-Programming Cancerous Brain Tumours to behave Less Aggressively

A2002565

Despite years of research, patients with malignant gliomas (GBMs) still face a poor prognosis, with a mean survival of 15 months. In contrast, patients with low-grade gliomas may survive many years, as these tumours harbour a unique molecular genetic signature – mutation of the IDH gene (IDHm). This mutation results in high levels of the metabolite 2-HG, causing multiple epigenetic changes, metabolic reprogramming, and an altered immune response around the tumour. Clinically, this decreased immune response is evident as patients with IDHm tumours do not experience brain swelling, while patients with GBMs usually suffer significant swelling and require steroid treatment.

No scientific team has attempted to treat GBM tumours by exposing them to 2-HG, with the hope of reprogramming them to behave less aggressively. To achieve this goal, a system is needed to study the effect of 2-HG on tumour cells, as well as on “normal” brain cells and “immune cells.” This is not possible in simple 2D cell cultures but is feasible using brain organoids – self-organising, three-dimensional tissue cultures that allow the study of tumour cell invasion and growth in a “mini-brain.”

Patients will be consented, and fresh GBM brain tumour tissue, taken at surgery, will be inoculated into a brain organoid (“mini-brain”), along with “immune” cells taken from a blood sample from the same patient. To this culture system, 2-HG will be administered daily, and the “mini-brain” will be harvested to analyse how the tumour and immune cells have behaved.

This novel concept, if proven effective, could significantly impact the direction of research in this field – aiming to epigenetically change malignant brain tumours so that they behave in a less aggressive manner

Lead Researcher	Mr Paul Chumas
Co-Researchers	Dr Heiko Wurdak Mr Ryan Mathew
Host Organisation/ CSU	Neurosciences Leeds Teaching Hospitals NHS Trust
Grant Amount	£9,990
Start Date	01/01/2024
Estimated Estimated Duration	11 months
Status	In Progress
Impact Areas	Health Inequalities – Cancer Care
Tags/key notes	Cancer and neoplasms