Introduction: Glioblastoma (GBM) is the most common and aggressive primary brain tumour, with a median survival of 15 months and a five-year survival rate of less than 10%. Despite aggressive treatment strategies such as the Stupp protocol (maximal safe surgical resection, radiotherapy [RT], and concomitant temozolomide [TMZ]), GBM remains a neurologically destructive and lethal disease. A mediator of GBM invasiveness are the actin-rich membrane projections on cancer cells known as invadopodia. These structures degrade the extracellular matrix, facilitating tumour cell invasion into normal brain. Our study will investigate the repurposing of FDA-approved drugs to reduce cell viability and inhibit invadopodia activity in GBM cells that survive the Stupp protocol.
Methods: Our study is investigating the effects of four FDA-approved drugs—vinorelbine, fluoxetine, flunarizine, and quinine (not previously used for the treatment of GBM patients) —in single/combinatorial treatments. We will utilise various assays including MTT assays, western blotting, zymography, and invadopodia-mediated FITC gelatin degradation assays to identify combinations that best reduce GBM cell viability and invadopodia formation/activity. Additionally, we will assess these combinations in conjunction with RT/TMZ to determine their impact on cell viability and post-RT/TMZ enhanced invadopodia activity. Promising combinations from the early experiments on the parental cell lines will be further tested on long-term treated GBM cells that have undergone 10 rounds of RT/TMZ treatment.
Results: So far, our study has confirmed that GBM cell lines increase the formation of invadopodia (FITC-gelatin degrading and non-degrading), with increased FITC-gelatin degrading activity observed after only a single dose of RT/TMZ (2 Gy/50 µM). This finding indicates that the increased invadopodia activity observed after RT/TMZ treatment may enhance GBM invasiveness in the surviving cells. Furthermore, preliminary results are already showing a significant reduction in GBM cell viability when certain FDA-drug combinations are coupled with RT/TMZ.
Conclusion: To date, our study results show potential for the repurposing of our four FDA-approved drugs, due to the reduction in GBM cell viability and invadopodia activity with certain combinations. These findings provide a foundation for the future incorporation of invadopodia-targeting therapies into existing treatment protocols, with the potential to improve patient outcomes in this fatal disease.