Brain tumors in children are the most common cause of cancer-related death in children – we need new therapeutic approaches. Here Dr. Lisa Ruff, why drug delivery is so important in the treatment of tumors of the central nervous system – and why hydrogels could be the key to a breakthrough …
Among pediatric cancers, central nervous system tumors are the most common form of solid cancers, accounting for up to 25% of pediatric tumors. Of these, brain tumors are the leading cause of cancer-related death.
Ependymomas are the third most common brain tumor in children and are incurable in up to 40% of cases. The standard of care for ependymomas has not changed in the past 40 years as patients receive a combination of surgical tumor removal and radiation therapy. There is therefore a clear need to develop new therapeutic approaches to improve both the survival and quality of life of children with ependymomas.
However, the use of chemotherapy has been limited by the resistance of the ependymomas and poor access to tumors beyond the blood-brain barrier (BBB). This is where new approaches to drug release could really show an effect.
More than one type of tumor …
Ependymomas are primary tumors of the central nervous system that arise 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 considered a single disease group because of their histopathological similarities. However, extensive studies by several research groups have shown that ependymomas comprise at least nine different subgroups, all of which are characterized by different molecular characteristics.
“Our hope is that this will not only apply to approved drugs – once established, the system could then be used for the administration of novel active substances.”
Because the subgroups respond differently to current therapy and clinical outcome, it is likely that each subtype will require individual treatment. A subgroup found in the forebrain is characterized by a novel fusion protein called ZFTA-RELA. It was first described by our group and acts as a potent driver of oncogenesis, which leads to a particularly poor prognosis.
Although advances in technology have optimized standard treatments, 10-year overall survival of pediatric ependymoma, and particularly ZFTA-RELA fusion-driven ependymoma, is poor.
While a number of new and FDA-approved drugs are effective against ependymoma cells in vitro, they fail in vivo and in clinical trials due to poor BBB penetration. For this reason, my laboratory is interested in a new drug delivery system for FDA-approved drugs. If we can receive therapies through the BBB, we hope to improve outcomes for patients.
And we hope that this does not only apply to approved drugs – once established, the system could then be used for the delivery of novel active substances.
Hydrogels as vehicles for drug delivery
During my doctorate, I worked on optimizing a drug delivery system that uses biodegradable hydrogels. I investigated the possibility of introducing effective anti-ependymoma drugs into the postoperative cavity of the supratentorial ependymoma. The hydrogels used for this project were developed in the laboratory of Professor Oren Scherman in the Department of Chemistry at the University of Cambridge. The gels are based on hyaluronic acid, a main component of the extracellular matrix in the brain. As a result, the gels can be broken down by enzymes – hyaluronidases – which are also expressed in the brain and, above all, are expressed in a number of brain tumor cells.
After a number of in vitro drug release studies, we had to test these gels in the preclinical setting. These studies were carried out in our preclinical mouse hospital – a platform developed by our laboratory that enables the testing of therapy combinations, such as those found in human patients, in preclinical brain tumor models.
Once it was clear how this drug delivery method should be used during neurosurgery, various preclinical studies enabled me to examine the drug release into the brain parenchyma – neurons and glial cells. It was also important to test the effectiveness of the hydrogel-based drug delivery after surgery in preclinical models of ependyma. In these studies, models were used for both ZFTA-RELA fusion positive and negative subgroups. The results of these studies have been very encouraging and multimodal preclinical studies are currently being conducted to understand how effective resection surgery could be when combined with hydrogel-based drug delivery and radiation therapy.
Hydrogels are a cross-linked hydrophilic polymer that does not dissolve in water. They are very absorbent and can maintain well-defined structures.
The great advantage of hyaluronic acid-based hydrogels, besides their biodegradability, is the fact that their viscosity allows them to easily mold themselves into resection cavities, which enables complete coverage of the walls within the cavity. Another advantage is that the mechanical properties of the hydrogels we use can not only be tailored to the transport of various active ingredients, but also to modify the active ingredient release to a desired rate. This is important because the drug release rate can be adjusted depending on how many tumor cells remain in the vicinity of the cavity and how quickly tumors recur.
When combined with FDA-approved drugs, this technique can be accelerated in clinical trials as it is a promising new technique that enables localized delivery of drugs that are highly effective against brain tumor cells but have poor BBB penetrability.
Because the treatment of ependymoma patients has not changed in the past 40 years, effective chemotherapy given through a local drug delivery system could mean better survival rates for children with the disease. In addition, this technique can be used on a wide variety of brain tumors whose standard of care includes surgical removal of the tumor.
Dr. Lisa Ruff received her PhD from the Cambridge Institute Cancer Research UK and was part of the CRUK Children’s Brain Tumor Center of Excellence. Today she is a postdoc at the German Cancer Research Center DKFZ.