Identification of potential drug targets in glioblastoma using proteogenomic platforms

Glioblastoma Multiforme (GBM) is a solid tumour of the central nervous system. To this date, it is the most aggressive primary brain tumour in adults, and few therapeutic solutions are available. This, in addition to the aggressiveness of the tumour, determine a low survival rate in patients. The World Health Organisation (WHO) classifies glioma in four grades with GBM being the highest-grade glioma. GBM is also classified according to the tumour mutations in three groups: MGMT mutated, EGFRvIII mutated and 1q19p co-deletion. Incidence increases with age and sex, in fact, males are more often affected. The risk of developing GBM is associated with very few genetic predispositions and environmental factors. Like other forms of solid tumours, glioblastoma goes undetected by the immune system due to the establishment of an immunosuppressive environment. The induced im munosuppression is caused mainly by GBM stem-like cells (GSCs), or tumour-initiating cells that are thought to be responsible for tumour maintenance, progression, recurrence, and resistance to therapy caus ing a major dilemma for immunotherapy and new drugs development. GSCs cells reside in multiple sites located inside the tumour mass characterised by hypoxia, acidic stress, and/or glucose restriction. Hypoxia has been shown to promote a stem-like state in tumour cells by activating pro-migratory and pro-invasive factors. Therefore, modulating its mechanisms could contribute to the development of therapeutic agents capable of targeting GSCs stemness. This PhD project forms a genomics expression platform using GSCs aimed at determining whether mutated signalling pathways and/or hypoxia-induced genes could form potential therapeutic targets for GBM. By understanding these three features; the nature of the mutation status of GSCs using genomics platforms that define RNA and DNA mutations; the impact of chronic hypoxia exposure on GSCs; and assessing mutated and non-mutated transcriptional and proteomic changes; we propose potential targets to be further investigated for the drug discovery of glioblastoma.

Grantor dc:publisher

The University of Edinburgh

Year dc:date.issued

2024

Author dc:creator

• Esposito, Estefania

Advisors dc:contributor.advisor

• Hupp, Ted
• Brennan, Paul

• Glioblastoma
• GBM
• immunotherapy
• brain tumor
• cancer
• macrophages

Language dc:language.iso

en

Identifier URI

http://dx.doi.org/10.7488/era/4891

OAI identifier oai:identifier

oai:era.ed.ac.uk:1842/42170