An Evaluation of Transforming Growth Factor-β Signalling in Adult Glioblastoma

Abstract

Introduction: Adult glioblastoma (GBM) is an aggressive and fatal primary brain malignancy, for which surgery, radiotherapy and temozolomide (TMZ) have been the standard of care for over two decades. Novel therapies are required, with the ubiquitous and essential cytokine, transforming growth factor-beta (TGFβ), being a promising therapeutic strategy of unharnessed potential. Here, the role of TGFβ signalling in GBM and the modulation of this signalling pathway as a potential therapeutic target is reviewed.

Materials and Methods: A bioinformatic analysis of canonical TGFβ genes in cancer and in GBM was carried out using karyotyping, mutation data and mRNA expression data to demonstrate the potential of specific genes within the pathway. This was performed using Microsoft Excel and GraphPad Prism. The small proteoglycan decorin (DCN) was then explored as a potential therapeutic using in vitro cell biology assays, namely proliferation assays and Western blotting.

Results: The bioinformatics data highlighted TGFβ2, SMAD7 and SARA as potential targets for GBM therapy. Using recombinant DCN in vitro to then modulate TGFβ signalling did not have a demonstrable effect on GBM cell proliferation. Interestingly, preliminary data suggest that DCN abrogates the efficacy of TMZ.

Conclusions: These in silico and in vitro data highlight that TGFβ signalling is a promising but context-dependent target. Of note, the interplay between DCN expression and TMZ efficacy remains to be fully elicited.

Date of Award	2019
Original language	English
Supervisor	Gareth Inman (Supervisor) & Kismet Hossain-Ibrahim (Supervisor)