Advances in glioblastoma: Is there light at the end of the tunnel?

Incremental gains:

Temozolomide remains the backbone of systemic therapy, particularly in patients with O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation.¹ Alternative regimens, including dose-dense or metronomic schedules, have been explored but with limited success.⁶

Antiangiogenic therapy, particularly bevacizumab, initially generated enthusiasm due to radiographic response and improved progression-free survival. However, robust evidence has failed to demonstrate a meaningful overall survival benefit.⁷ The Cochrane review by Khasraw et al⁷ highlights the limitations of antiangiogenic strategies, emphasising transient benefits and the development of resistance.

These findings reinforce the notion that targeting a single pathway in a biologically heterogeneous tumour like glioblastoma is unlikely to yield durable results.

Promise tempered by complexity:

The success of immune checkpoint inhibitors in other malignancies has spurred interest in their application to glioblastoma. However, results have been largely disappointing. The recent Cochrane review evaluating anti–PD-1 and anti–PD-L1 therapies found insufficient evidence to support their routine use in glioblastoma.⁸ Several factors contribute to this limited efficacy, including the heterogeneity of tumour and microenvironment cells, low mutational burden, inadequate pharmacokinetic properties of agents, and the presence of the blood-brain barrier.⁹ Nevertheless, ongoing trials exploring combination approaches—such as checkpoint inhibitors with vaccines, radiotherapy, or oncolytic viruses—offer cautious optimism. Emerging immunotherapeutic strategies include dendritic cell vaccines, CAR-T cell therapy targeting Epidermal Growth Factor Receptor variant III (EGFRvIII), and tumour lysate-based vaccines.¹⁰ While early-phase trials have shown signals of activity, these approaches remain investigational.

Molecular and cellular insights:

Advances in molecular profiling have transformed our understanding of glioblastoma, revealing its profound heterogeneity. The identification of key molecular subtypes and pathways, including epidermal growth factor receptor (EGFR) amplification, changes in cyclin and cyclin-dependent kinases (CDK), retinoblastoma, and p53 pathways, has provided potential therapeutic targets.¹¹ However, translating these insights into effective therapies has proven challenging.

One of the more intriguing avenues is the modulation of autophagy, a cellular process involved in tumour survival and resistance. Preclinical and early clinical studies suggest that both activation and inhibition of autophagy may have therapeutic potential, depending on the context.¹² This duality reflects the complexity of glioblastoma biology and highlights the need for precision approaches.

Similarly, theranostics, tumour metabolism, epigenetic regulation, and the glioma stem cell niche are being actively investigated.^13-16 These areas may offer opportunities for disrupting tumour resilience and recurrence.

The unmet frontier:

Management of recurrent glioblastoma remains particularly challenging, with no established standard of care. Median survival for recurrent disease is 6-9 months. Options include reresection, reirradiation, chemotherapy, and enrolment in clinical trials.^4,6 The review by Aldoghachi et al⁶ emphasises the need for multimodal strategies tailored to individual patient characteristics. Importantly, patient selection and quality-of-life considerations are critical in this setting.