Delivering the future of paediatric brain tumour therapy

Among paediatric cancers, tumours developing in the central nervous system are the most frequent form of solid cancer, accounting for up to 25% of paediatric tumours. Of those, brain tumours are the leading cause of cancer-related deaths.

Ependymomas are the third most common paediatric brain tumour, incurable in up to 40% of cases. Standard of care treatment for ependymomas has not changed over the last 40 years with patients receiving combinations of surgical tumour removal and radiation therapy. There is a clear need then to develop novel therapeutic approaches to improve both the survival, and the quality of life for children with ependymomas.

However, use of chemotherapy has been limited by the resistant nature of ependymomas and poor access to tumours behind the blood brain barrier (BBB). It is here that novel approaches to drug delivery could really have an impact.

More than one tumour type…

Ependymomas are primary tumours of the central nervous system arising from radial glial stem cells. They generally form near the ventricles of the brain and the central canal of the spinal cord.

Until recently, ependymomas were regarded as a single disease group due to their histopathological similarities. However, extensive research by a number of research groups revealed that ependymomas comprise at least nine different subgroups, all of which are characterised by different molecular features.

“Our hope is that this won’t only be applicable to approved drugs – once established, the system could then be used for the delivery of novel compounds.”

As the subgroups have differing responses to current therapy and clinical outcome, it is likely each subtype will need individual treatments. One subgroup, occurring in the forebrain, is characterised by a novel fusion protein called ZFTA-RELA. It was first described by our group and acts as a potent driver of oncogenesis, resulting in a particularly poor prognosis.

Although advances in technology have optimised standard of care treatments, the 10-year overall survival of paediatric ependymoma, and particularly the ZFTA-RELA fusion driven ependymoma, is poor.

While a number of novel and FDA-approved drugs are effective against ependymoma cells in vitro, they are failing in vivo and in clinical trials due to poor BBB penetration. This is why my lab is interested in a new drug delivery system for FDA-approved drugs. If we can get therapies through the BBB, then we hope to improve the outcomes for patients.

And our hope is that this won’t only be applicable to approved drugs – once established, the system could then be used for the delivery of novel compounds.

Hydrogels as drug delivery vehicles

During my PhD, I looked at the optimisation of a drug delivery system that utilises biodegradable hydrogels. I studied the feasibility of delivering potent anti-ependymoma drugs into the post-surgical cavity of supratentorial ependymoma. The hydrogels used for this project were developed in Professor Oren Scherman’s lab at the Department of Chemistry, University of Cambridge. The gels are based on hyaluronic acid, a major component of the extracellular matrix in the brain. As a result, the gels can be degraded by enzymes – hyaluronidases – also expressed in the brain and, importantly, have been shown to be expressed in a number of brain tumour cells.

Following a number of drug-release studies in vitro, we needed to test these gels in the preclinical setting. These studies were performed in our preclinical mouse hospital – a platform developed by our lab, which allows for the testing of combinations of therapies, such as those experienced by human patients, in preclinical brain tumour models.

Once it was clear how to use this drug delivery method during neurosurgery, a variety of preclinical studies allowed me to investigate the drug release into the brain parenchyma – neurons and glial cells. It was also important to test the efficacy of the hydrogel-based drug delivery post-surgery in preclinical ependymoma models. Models for both ZFTA-RELA fusion-positive and -negative subgroups were used in these studies. The results from these studies were very promising and multimodal preclinical studies are currently ongoing to understand how effective resection surgery combined with hydrogel-based drug delivery and radiation therapy could be.

The great advantage of the hyaluronic acid-based hydrogels besides their biodegradability is the fact that their viscosity allows them to easily mould into resection cavities, therefore allowing for total coverage of the walls within the cavity. Another advantage is that the mechanical properties of the hydrogels we are using can be tailored not only to carry different drugs but also to modify drug release to a desired rate. This is key, because the release rate of the drug can be tailored depending on how many tumour cells remain in the cavity surroundings and how fast tumours recur.

When combined with FDA-approved drugs, this technique can be accelerated into clinical trials as it presents a promising novel technique, which allows for the localised delivery of drugs that are highly active against brain tumour cells but display poor BBB penetrability.

As the treatment for ependymoma patients has not changed in the last 40 years, an effective chemotherapy, delivered via a local drug delivery system could mean a better survival rate for children with this disease. Moreover, this technique can be applied to a variety of brain tumours whose standard of care includes surgical removal of the tumour.

Author:
Dr Lisa Ruff completed her PhD at the Cancer Research UK Cambridge Institute, and was part of the CRUK Children’s Brain Tumour Centre of Excellence. She is now a Postdoctoral Researcher at DKFZ German Cancer Research Center.