A new triple treatment for a very aggressive brain cancer

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The Inserm

Glioblastoma is the most common and aggressive brain tumor. It can develop at all ages, and concerns about 3000 people each year in France. Despite treatments that combine surgery, radiotherapy and chemotherapy, life expectancy is only fifteen to eighteen months. The failure of treatments can be attributed to the difficulty of reaching and circumscribing such tumors during an operation, but also to the fact that current treatments have the defect of not being selective. That is, they attack many healthy cells at the same time as the cancer cells. In order to act effectively on the tumor, it would be necessary to prescribe the drug in dosages which would have devastating effects on the body and brain of the treated patients. The challenge is to improve the results of chemotherapy while preserving healthy cells. For this, researchers associated Inserm and the National Institute of Applied Sciences (INSA) Center-Val de Loire, coordinated by the neurobiologist Joel Eyer, University of Angers, imagined a device of a new genre .

Penetrate the cancer cells

The project is based on the results of neurobiologist Joel Eyer and his team’s research in recent years. These focused on the structure of neurons and a synthetic peptide , a sequence of 24 amino acids developed by mimicking the structure of the cytoskeleton of nerve cells. This peptide has a chemical constitution that allows it to penetrate the membrane of cancer cells, while it has no influence on healthy cells, astrocytes and neurons. The reasons for this selectivity are not yet clear; but researchers suspect that it is linked to the presence of lipids and phospholipids enriched in glioblastoma cells, which are not found in healthy cells.

The therapeutic molecules will be loaded aboard lipid nanocapsules (kinds of capsules of nanometric size, that is to say a hundred times finer than a hair) or nano-vehicles made of porous silicon, biocompatible nano-sponges whose Pores can be filled with different kinds of particles. Thus, the administration of chemotherapy could be much more targeted, because the nanocapsules could penetrate inside the cells using the peptide as docking arm to the cancer cells.

In addition to its selectivity, this peptide is in the image of many molecules used in chemotherapy an anticancer drug : it interacts with tubulin, the structural protein of microtubules, a major constituent of the cell cytoskeleton. This stops the mitosis (division) of the cells it enters, and thus prevents the development of the tumor and metastasis. It has the advantage, compared to most other anticancer drugs, to attack the stem cancer cells, which are the most difficult to destroy, and to act on all types of glioblastomas tested so far: because mutations The cause of this cancer is numerous, and conventional drugs are only effective on some of them.

In 2013, the peptide was tested by Eyer and his team in vitro and in vivo , with very encouraging results: in rats carrying a gioblastoma (that is to say, which were implanted cancer cells), administration greatly slowed the progression of the cancerous tissue: the volume of the tumor was reduced by 60%. The combination of the peptide with another anticancer drug, Paclitaxel, resulted in a 75% reduction in tumor volume . Eyer’s current research and his team are focused on a combination therapy that combines the effectiveness of this peptide with that of other chemotherapeutic molecules in nanocapsules, specifically targeting glioblastoma cells. This therapy has so far been tested only on rodents, but the goal of the researchers is of course to apply it eventually to humans.

Bring nanocapsules to port

During rodent testing, the peptide and nanocapsules were injected directly into the tumor site. But injecting the drug locally would not work as part of a therapy for humans. Firstly because glioblastoma is often in diffuse form, that is to say in the form of cancerous cells scattered in the brain, which makes local injection treatment impossible. Secondly, repeated injections could make cancer metastasize. Therefore, it is necessary to stick to an intravenous administration.

However, the routing of treatment to the brain is problematic. It is necessary to avoid the dispersion of the treatment in the rest of the organism on the one hand, and to pass the blood-brain barrier (which protects the brain from the pathogens present in the general blood circulation) on the other hand. To overcome this second problem, researchers from the Eyer team have teamed up with nanorobotics specialists from INSA Center Val de Loire, led by Antoine Ferrera.

Their idea is to match the nanocapsule / peptide complex with a particle of magnetite, an iron oxide with magnetic properties. The tiny therapeutic vessels will then be injected into the bloodstream and guided to the brain through a robotic system based on the principle of magnetic resonance, which is widely used in medical imaging (MRI). Electromagnets will control the movement of magnetic particles in the blood by varying very finely the magnetic field. To monitor the process, the nanocapsules will be provided with a phosphorescent element, in order to be able to follow them in real time, and thus make up for possible errors of trajectory.

The magnetization of the nanocapsules also offers a solution to the problematic passage of the blood-brain barrier: the researchers plan to use magnetic resonance to locally heat the magnetite particles, which will have the effect of expanding the pores of the barrier and allowing the passage nanocapsules. This technique could even complete the therapeutic effectiveness of the peptide and nanocapsules: once the treatment arrived in glioblastoma cells, to pass the temperature of cancer cells from 37 ° to 45 ° would kill them.

This device will begin to be tested on rats from the beginning of 2019. It is hoped that the results will be conclusive. If this is the case, this technique could be applied to other brain pathologies such as Alzheimer’s disease, or stroke.

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