Using genetic evidence to identify novel drug targets for the treatment of glioma

Abstract

Glioma is the most common tumour of the central nervous system and results in the most significant years of life lost from any malignancy. Current treatment of glioma still leads to poor prognosis and clinical outcomes, particularly in high-grade glioma. Additionally, there are only two well-established risk factors associated with gliomagenesis, and whilst many more are currently postulated, there is conflicting evidence in the literature.
The overarching aim of this doctoral thesis was to use a number of analytical, epidemiolocal methods to provide evidence for repurposing existing drugs for the treatment of glioma, and to use both causal and non-causal evidence to identify potential novel drug targets in the prevention of glioma.
In Chapter 4, I conducted a systematic review of case reports, case series and uncontrolled trials to establish the efficacy of a pre-existing class of drugs, BRAF inhibitors, in the treatment of BRAF V600 mutation-positive glioma. Results showed that BRAF inhibitors had a positive effect on median progression free survival in paediatric patients compared to adult patients, and in low-grade glioma compared to high-grade glioma.
In Chapter 5, I used a Mendelian randomisation-colocalisation framework to provide causal evidence for germline genetic variants associated with gene expression, gene splicing variation and protein abundance and their effect on glioma risk. These analyses found 22 molecular traits across 18 genes/proteins, of which five were novel and causally implicated in the risk of gliomagenesis: CEP192, D2HGDH, FAIM, HBEGF and SLC8A1.
In Chapter 6, I estimated the genome-wide and local-level genetic correlation between 21 extracranial cancers and glioma, with particular focus on breast carcinoma, colorectal carcinoma, kidney carcinoma, lung carcinoma and cutaneous melanoma, which have a higher likelihood of metastasising to the brain or CNS. Several investigative methods including were used to annotate and prioritise genetic loci and genes: MDM4, TERT, CDKN2B, TNFSF13 and TP53, which may be implicated in the aetiology and genetic architecture of glioma.
Overall, these analyses collectively provide evidence for the repurposing of pre-existing drugs in the treatment of glioma (Chapter 4), for the identification of putative novel drug targets for the prevention of glioma (Chapter 5), and insight into the genetic architecture of glioma which highlights the biological pathways which may be implicated in the risk of glioma (Chapter 6).

Date of Award	18 Mar 2025
Original language	English
Awarding Institution	University of Bristol
Supervisor	Kathreena M Kurian (Supervisor), Lavinia Paternoster (Supervisor) & Jamie W Robinson (Supervisor)