Repurposing antipsychotic drugs for brain tumour treatment

Dr Noor Gammoh noor.gammoh@ed.ac.uk

Funding information (students eligible to apply): UK/International students

Project Description

Glioblastoma multiforme (GBM) is the most common and devasting brain tumour. Despite extensive research, treatment advancements over the past decade have been limited. Our lab is interested in understanding the role of lysosomal degradation in cancer. We have shown that autophagy, a lysosomal cargo delivery mechanism, is important for glioblastoma growth and survival. Although there is compelling genetic evidence suggesting that autophagy promotes the survival and resistance to treatment of multiple cancers, its therapeutic modulation remains challenging due to the lack of effective and non-toxic inhibitors. 

A recent screen in our lab identified a panel of psychotropic agents as potent inhibitors of autophagic degradation and inducers of cell death. Interestingly, glioma stem cells (GSCs) appeared to be more sensitive to treatment with most psychotropic agents compared to normal stem cells (NSCs). These small molecules accumulate in lysosomes and disrupt their function. Importantly, two structurally related molecules that are also lysosomotropic did not elicit cell death in GSCs highlighting a degree of specificity and target engagement. Given that the identified psychotropic agents can cross the blood-brain barrier (BBB) and are well tolerated in humans, they present a promising opportunity for drug repurposing in GBM therapy.

This PhD project aims to further explore the potential therapeutic use of the psychotropic agents in GBM treatment. The main aims are as follows:

1. Investigate the sensitivity of patient-derived cells to treatment with psychotropic agents.
2. Identify lysosomal targets that render cells sensitive to death upon drug binding.
3. Test the release of immunogenic factors associated with lysosomal inhibition.
4. Evaluate the therapeutic potential of these agents in suppressing GBM growth and immune cell recruitment in preclinical models.

By integrating molecular mechanism studies with disease modelling, this project aims to advance new therapeutic strategies for GBM treatment.

References

1. Simpson JE, Muir MT, Lee M, Naughton C, Gilbert N, Pollard SM, Gammoh N (2024) Autophagy regulates PDGFRA-dependent brain tumour development by modulating oncogenic signalling. Developmental Cell 59(2):228-243.e7
2. Makar AN, Boraman A, Mosen P, Simpson JE, Marques J, Michelberger T, Aitken S, Wheeler AP, Winter D, Kriegsheim A, Gammoh N (2024) The V-ATPase complex component RNAseK is required for lysosomal hydrolase delivery and autophagosome degradation. Nature Communications 15(1):7743
3. Debnath J*, Gammoh N*, Ryan KM* (2023) Autophagy and autophagy-related pathways in cancer. Nature Reviews Molecular Cell Biology 2:1-16
4. Fraser J, Simpson J, Fontana R, Kishi-Itakura C, Ktistakis NT, Gammoh N (2019) Targeting of Early Endosomes by Autophagy Facilitates EGFR Recycling and Signalling. EMBO Reports 26: e47734

Subject areas

Cancer Biology; Cell Biology; Molecular Biology; Pharmaceutical Chemistry