Research And Grants

Targeting Top3A-Amplified DIPG cells by Sirtuin inhibition.

Diffuse intrinsic pontine glioma (DIPG) is a malignant brainstem tumour arising in children representing a major unmet clinical need, with a 2-year survival rate close to zero. With chemotherapy ineffective and surgical intervention not possible, new therapeutic approaches are urgently required based upon the unique biological mechanisms driving DIPG tumorigenesis. We recently discovered amplification of the gene TOP3A to play an important role in a proportion of DIPGs. Critically, cells driven by this genetic alteration to be exquisitely sensitive to inhibitors of sirtuin, which appears to link TOP3A to DNA repair. We plan to explore this in more detail by turning off, and/or turning on the gene in DIPG cells, in order to better understand it’s precise function. We will also screen a range of drugs known to target sirtuins, in order to determine which may be most useful in the clinic, both in cells grown in the laboratory as well as using patient-derived mouse models. We will further look for possible combinations with sirtuin inhibitors in order to further enhance the potential for rapid translation.