Every year, some 500 to 700 people in the Netherlands are diagnosed with glioblastoma. Neither surgery, radiotherapy, nor chemotherapy have yet provided a cure for this form of brain cancer. The challenge faced by surgical and radiotherapy teams is that the tumors are not sharply defined and invade deep into the surrounding brain tissue. The challenge for drug-based therapy is that glioblastoma cells are very effective in developing resistance. Even novel immunotherapy approaches – which have proved impressively successful in other solid tumors – have failed in the case of glioblastoma. This is largely due to a highly suppressive tumor microenvironment, where the tumor-associated macrophages effectively ‘hijack’ the local immune response.
In search of a solution, the Cat4CanCenter project takes a radically new approach. It combines the efforts of Prof. Joost Reek, an expert in catalysis at the UvA, Dr Leila Akkari, a cancer immunologist at the Netherlands Cancer Institute (NKI) and Oncode Institute, and Prof. Alexander Kros of Leiden University, specializing in drug delivery. Together, they propose a pioneering form of chemotherapy in which active, toxic drugs are synthesized in the tumor environment itself. To enable this, first, a molecular catalyst is delivered into the tumor tissue using lipid nanoparticles. Then pro-drug molecules are administered. Finally, the catalyst converts these non-toxic precursors into active drugs that will fight the glioblastoma ‘from within’.
The advantage of this approach is that the tumor can be ‘loaded’ with high levels of drugs without the adverse effects normally associated with drug treatments. Current therapies involve administering high doses in the bloodstream to ensure that enough drugs can cross the blood-brain barrier and arrive at the brain tumor site. The resulting active dose in the tumor is typically relatively low, however, while the high dose in the blood results in concurrent toxicity and off-target side effects. By using non-toxic compounds, the new approach avoids these often severe complications.
The novel Cat4CanCenter approach also requires the components to cross the blood-brain barrier and to hit specific cell types in the tumor. For the pro-drugs, this can be achieved through a dedicated molecular design. For the catalyst, this is ensured by using lipid nanoparticles that can carry compounds from the blood to the brain. This is the expertise of Prof. Kros. “The brain is protected from foreign (bio)chemicals by the blood-brain barrier,” he explains. “It has proven to be a formidable barrier, rendering state-of-the-art drug delivery approaches that are successful in other therapies ineffective. In Cat4CanCenter we develop radical new approaches to bring the catalysts inside the tumor by hijacking currently unexplored biological pathways that are already present in the human body.”