Jeroen Goos awarded with starting Grant

The grant is directed to the project "Tearing down the walls of brain cancer: delivery of radiopharmaceuticals across the blood-brain barrier"

One in three children that suffer from brain cancer dies before reaching adulthood. Standard treatment generally involves the opening of the skull for physical removal of the tumour, often in combination with several cycles of chemo- and/or radiotherapy. Brain surgery is highly invasive and comes with significant risks. Risks include bleeding or blood clots in the brain, swelling, memory problems, seizures, infections, stroke, coma and impaired speech, vision, coordination or balance. Furthermore, it is often difficult for a surgeon to identify where the tumour ends and healthy tissue begins. Surgery is only effective when the tumour is fully removed, since an incomplete resection will lead to relapse, and decreases the survival chances of a patient. In the current project, we are developing an innovative, non-surgical treatment strategy that minimises side effects with a substantial chance of significant tumour reduction or complete tumour elimination.

A promising non-surgical treatment strategy: endoradiotherapy

In the field of endoradiotherapy, tumour-targeting molecules such as antibodies or peptides are labelled with radioactive isotopes to deliver a lethal dose of radiation to a tumour. These radiolabelled molecules are injected into patients with cancer to bind to tumour cells and irradiate the tumour from within. With this treatment, the number and size of tumours can significantly be reduced, which has led to a remarkable increase in survival rates. A major limitation in the scope of brain cancer, however, is that standard endoradiotherapeutic agents cannot cross the blood-brain barrier (BBB). This is a layer of tightly packed cells that separates the brain from the blood circulation to protect it from toxins and other pathogens. The first goal of this project is to design endoradiotherapeutic agents that can cross the BBB and target the brain tumour. As a first strategy, we are developing an innovative bispecific antibody that can be transported across the BBB to specifically bind to brain tumour cells. Here, we combine a tumour-targeting antibody with parts of a second antibody that enable transportation across the BBB. As a second strategy, we are using a peptide from scorpion venom, which is designed by nature to cross the BBB to target the central nervous system. In preclinical studies, this peptide has demonstrated an exceptionally high specificity for brain tumour cells.

Minimising side effects

Antibodies and peptides generally circulate in the body for multiple days. In the case of radiolabelled antibodies and peptides, this leads to undesirably high radiation doses to healthy tissues. Particularly in children, this may lead to significant side effects, such as impaired bone growth, calcium deficiency and toxicity to the haematopoietic system. The second goal of this project is to reduce side effects by separately injecting the bispecific antibody or peptide and the radioactive agent, which then chemically react to each other at the tumour site. The advantage of this pretargeting strategy is that long-circulating, unbound antibodies and peptides are cleared from the body before the radioactive agent is injected. This radioactive agent is cleared from the body rapidly, thereby minimising the radiation dose to healthy tissues. With this strategy, we aim to deliver a high therapeutic radiation dose to the brain tumour, while minimising the side effects caused by radiation to the rest of the body.

Innovative research

Our research integrates recent advances in radiology, oncology, chemistry and molecular biology into innovative research designs and novel treatment strategies. This project will open up new fields of research and allow children with brain cancer to benefit from the exceptional proven clinical advantages of endoradiotherapy, with minimal side effects. The newly designed methodologies and agents could lead to breakthroughs in key applications of fundamental, preclinical and clinical interest and change the way we approach illnesses of the brain.