This project combines three game-changing approaches to treating brain cancer: (1) a novel form of radiotherapy – known as FLASH radiotherapy – which uses a rapid, ultra-high dose rate radiotherapy beam. This shortens treatment time and minimises damage to healthy brain tissue (2) injection of a drug-loaded gel (called a hydrogel) into the tumour resection cavity to attack and kill residual cancer cells that could not be surgically removed and (3) the hydrogel loaded with a compound effective at attacking GBM stem cells, the tumour cells responsible for tumour recurrence.

This project aims to show the effectiveness of drug-loaded gel (known as hydrogel) as a therapy for brain cancer patients, and explore the effectiveness of combining the hydrogel treatment with a rapid, high-dose rate radiotherapy technology. For patients, this combined treatment approach has the potential to minimise treatment time for patients while sparing healthy brain tissue damage. Most importantly, the drug compound in this study has already been shown to effectively kill GBM and glioma stem cells known to drive recurrence, meaning this treatment approach may prevent tumour recurrence.

FLASH radiotherapy and radiation-responsive hydrogel drug delivery as a novel combination therapy for glioblastoma

Glioblastoma (GBM) patients, despite an aggressive treatment strategy, invariably have recurrence of the primary tumour, leading to death. Seeking improved treatments for GBM and the potential glioma stem cells (GSCs) implicated in recurrence, the team performed a high-throughput screen of a large bioactive drug library and found that the drug Quisinostat effectively targets GSCs and GBM cells at nanomolar concentrations. The team also tested this drug and confirmed efficacy in patient-derived GBM organoids and in mouse GBM models, however, the team observed dose-limiting systemic side effects. Therefore, the team now seek to leverage their collective expertise to develop a therapeutic strategy centered on administration of a radiation-responsive drug loaded hydrogel (RR-gel) to the tumour resection cavity. Such an approach will result in high concentrations of drug deposited directly to the target site, while avoiding unnecessary systemic doses to other organs. Furthermore, since radiotherapy is also part of the standard of care, a hydrogel that synergizes with radiation (e.g. increases the effects of radiotherapy and/or releases drug in response to radiotherapy) will improve treatment outcomes.

The team’s promising preliminary data shows that such a hydrogel can effectively control GBM tumours. Moreover, the team plans to integrate the hydrogel with FLASH radiotherapy, a novel form of radiotherapy that involves ultra-fast delivery of radiation treatment at dose rates several orders of magnitude higher than those conventionally used and has the potential to decrease normal tissue toxicity. The team proposes to develop improved versions of our radiation-responsive hydrogel system, characterize them and test them in vitro and in vivo for their anti-GBM efficacy, in combination with FLASH radiotherapy. The team will use spectral CT to monitor the hydrogel in vivo. The safety of the treatment will be extensively assessed. Overall, the team seeks to develop a breakthrough therapy for GBM.