Towards better treatments for glioblastoma

Abstract

Glioblastoma multiforme (GBM) is the most aggressive primary brain tumour in adults. Despite a multidisciplinary approach including surgery, concomitant radiation therapy, and chemotherapy to treat GBM, and extensive efforts to identify new therapeutic approaches, most patients experience poor prognosis limiting the median survival to under 15 months. This is mainly due to factors such as tumour heterogeneity, tumour microenvironment, blood-brain barrier (BBB), and DNA damage repair mechanism of the O6-methylguanine-DNA methyltransferase (MGMT) protein which leads to drug resistance and tumour recurrence. Cyclo-((2-Nal)-Leu-Ser-(2-Nal)-Arg) acetate (c2) is a novel synthetic compound that has been under investigation for prostate cancer in our lab, and sparked interest for GBM when it shows in vitro GBM cell killing. Interestingly, a preclinical pharmacology and toxicology study conducted on c2 revealed that c2 has a good safety profile in humans and animals, and some evidence that the drug may cross the BBB. This study was aimed at investigating the anti-GBM activity of mainly c2, and two other phytochemical compounds withaferin-A (WFA) and thymoquinone (TQ). To determine if c2 is a suitable drug candidate for GBM, we looked at its in vitro behaviour in two-dimensional (2D) and three-dimensional (3D) cell culture models, possible mechanism of action using a “bottom-up” proteomics approach, and a comprehensive study on BBB permeability using a rodent model. The results presented here show that the novel synthetic peptide c2, and the phytochemical compounds TQ and WFA are better at inhibiting GBM in various 2D, and 3D cell models compared to TMZ. Continued work on these compounds, including testing for any combinatory effects between the drugs would benefit GBM drug development. Knowledge generated in this thesis would allow for a deeper understanding into GBM and the development of “better” treatments for this devastating condition.

Date of Thesis submission	2024
Original language	English
Awarding Institution	Western Sydney University
Supervisor	David Harman (Supervisor), Shadma Fatima (Supervisor) & Kieran Scott (Supervisor)