Developing Novel Targeted Theraphies Towards High Grade Glioma by Using Omics Data Integration Approaches


Thesis Type: Doctorate

Institution Of The Thesis: Dokuz Eylul University, İzmir Uluslararası Biyotıp Ve Genom Enstitüsü, Turkey

Approval Date: 2023

Thesis Language: Turkish

Student: Fadime Öztoprak

Principal Supervisor (For Co-Supervisor Theses): Yavuz Oktay

Co-Supervisor: Zerrin Işik

Abstract:

Gliomas are the brain tumors that develop in glial cells and present severe

challenges based on intertumoral heterogeneity associated with different subtypes,

further leading to poor prognosis and outcomes for patients. This study was conducted

to utilize the transcriptomics and DNA methylation datasets available to researchers

to arrive at conclusions that can be utilized for either screening novel targets or use

already established drugs that can target the specific gene signatures associated with

low grade gliomas (LGGs), which develop into high grade gliomas (HGGs) or

Glioblastoma multiforme (GBM). We identified co-expression modules and their

associated pathways for specific subtypes of LGG IDH mut pTERT-, IDH mut

pTERT+, IDH wt pTERT-, and IDH wt pTERT+. We constructed co-expression

modules based on these subtypes and found common and different enriched pathways

as synapse pathways and immune-related pathways, respectively. We further explored

the differentially expressed genes (DEGs) and found a gene signature of upregulated

GNG12 and downregulated PLCB1, GRIA2, GABRA3, and GNAL after mapping

DEGs on our co-expression modules of interest. This gene signature was included in

our drug-gene interaction analysis, leading us to 4 drugs (Vemurafenib, Vanadium

Pentoxide, Imatinib, and Cisplatin,) that can target 4 out of 5 genes. Therefore, we

recommend exploring the synergistic effects of the combination of these drugs against

low and high grade gliomas. We also integrated transcriptomics and DNA methylation

data to develop networks including epigenetic factors that can be targeted in a subtype

specific manner. Our analysis revealed that PRMT5 can be used as a target irrespective

of the LGG subtype and WEE1 is a specific target for IDH wt regardless of pTERT

status. The specific chemical inhibitors of these targets being available could facilitate

translation of our findings into preclinical settings.