A novel approach proposed to improve the efficacy of chemotherapy against brain tumours
Scientists from the Institute of Biology and Biomedicine at Lobachevsky University and from Ghent University (Belgium), led by Prof. Dmitry Krysko, have proposed to increase the efficacy of Temozolomide - a chemotherapeutic drug used to treat an aggressive type of brain tumour (glioblastoma) - by activating several cell death pathways in the tumour. The proposed approach triggers mechanisms different from the action of Temozolomide that activate the immune system against the tumour. This will ensure an effective fight against drug-resistant cancer cells and the development of a close immune surveillance that prevents tumour recurrence. The results of the study, supported by a grant from the Russian Science Foundation (RSF), were published in Trends in Cancer.
Glioblastoma, a tumour affecting brain cells, is considered the most aggressive type of cancer. In the course of its treatment, patients undergo surgical removal of the tumour, followed by radiation therapy in combination with chemotherapy. The action of these methods is mainly aimed at damaging the DNA of the remaining cancer cells, which leads to their death and reduces the risk of tumour re-growth.
Temozolomide (“Temodal”) is the drug that is most often used in chemotherapy for patients with glioblastomas. Temozolomide has a number of advantages, in particular, it crosses the blood-brain barrier and penetrates into the brain tissue, directly acting on tumour cells. In addition, its side effects are well known and can be controlled in the clinic. However, for many patients, the effectiveness of such therapy is extremely low, because glioblastoma cells have some features permitting them to “fight back” the chemopreventive agent and develop resistance to it.
Lobachevsky University and Ghent University scientists have proposed to modify several cell death pathways in glioblastoma cells, thus reducing the likelihood of their developing resistance to Temozolomide. Triggering multiple cell death cascades would also potentially allow to target functionally different cells within the tumour. The researchers have already shown the feasibility of this approach in a number of studies using animals as experimental models.
According to the proposed approach, in parallel with the launch of the classical mechanism of Temozolomide action, an alternative pathway of cell death is activated, which has immunogenic properties: it helps the immune system to become a participant in the fight against the tumour. It can be activated by additional drugs or some physical effects, such as ultrasound.
When the immunogenic pathway of cell death is initiated, tumour cells release special “danger molecules” that attract specific cells of the immune system - dendritic cells - to the site of their death. These, in turn, absorb fragments of dying cells and “show the dying enemy” to T-lymphocytes. Similar cell fragments are also present in living cancer cells, which become targets for T-lymphocytes. As a result, a specific immune response is formed that destroys the glioblastoma cells remaining alive after therapy. In addition, the cells of the immune system subsequently begin to closely monitor the tumour to prevent recurrence.
The authors proposed to implement such a combined approach using nanocarriers that allow targeted delivery to the tumour of Temozolomide and other substances that are required to trigger immunogenic cell death. Targeted delivery will reduce possible side effects on healthy cells in the human body.
“Temozolomide is an attractive chemopreventive agent for the proposed combination therapy, which will improve the efficacy and quality of treatment for patients with glioblastomas. In the future, we plan to evaluate the efficacy of co-administration of Temozolomide and an activator of the iron-dependent form of cell death, whose high immunogenic potential we have shown in the course of our RSF project. We will also test the safety of our approach with respect to healthy brain cells, which will potentially allow us to assess the rationality of further preclinical and then clinical trials in humans,” says the project leader Tatiana Mishchenko, Associate Professor at the UNN Department of Neurotechnology.
