Cancer will be defeated: new method defeats resistance of aggressive brain tumor

Scientists have discovered that a short sequence regulating the activity of a certain gene plays a key role in the formation of resistance of the most aggressive brain tumor - glioblastoma - to the chemotherapeutic drug temozolomide. Experiments have shown that if you "block" the production of this molecule, tumor cells become sensitive to treatment. This opens the way to the development of new methods of oncotherapy.

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Glioblastoma is the most common and dangerous brain tumor, characterized by rapid growth and resistance to therapy. Even with a combination of surgical removal, radiation therapy and chemotherapy, the survival rate of patients during the next five years after treatment does not exceed 3-4%. One of the main reasons for low treatment efficacy is that cancer cells resist the action of the drugs. For example, the STAT3 protein is known to be involved in the formation of drug resistance in tumors. Theoretically, if you block its production, there is a chance to overcome the resistance of cancer cells, but it can disrupt the immune system, in which the protein is also involved.

Preparation of cells for analysis

Photo: Vadim Torgaev

Researchers from the V.A. Engelg Institute of Molecular Biology. V.A. Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences have proposed a safer approach - to affect the regulatory (enhancer) RNA, which controls the level of these molecules. The authors studied a short sequence (called TMZR1-eRNA), which is read close to the STAT3 gene and regulates the synthesis of the protein of the same name.

- Our study suggests a fundamentally new strategy to combat glioblastoma resistance to therapy. In contrast to direct suppression of STAT3, the impact on enhancer RNA is highly specific, so that drugs targeting this molecule, potentially will have fewer side effects, - told "Izvestia" the head of the project, supported by a grant from the Russian National Foundation, a researcher at the Institute of Molecular Biology of the Russian Academy of Sciences and a graduate student of MIPT Ekaterina Stasevich.

Biologists conducted experiments on laboratory-grown glioblastoma cell lines, as well as cells obtained from patients with this type of tumor. In these cells, the scientists artificially suppressed the RNA under study. They found that this intervention reduced STAT3 protein levels and increased the tumor's sensitivity to temozolomide, a popular drug for treating malignant tumors.

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The proposed approach has an important advantage: since the studied regulatory RNA, unlike the protein, is practically undetectable in healthy tissues (with the exception of muscle tissue), suppression of this molecule will not be accompanied by side effects.

Photo: provided by the Engelhardt Institute

- We have demonstrated for the first time that exposure to enhancer RNA allows selective suppression of STAT3 protein in glioblastoma cells. This is especially important, as this protein is involved in the immune system, and its systemic suppression can interfere with the antitumor effect, - told "Izvestia" candidate of biological sciences, a member of the laboratory of intracellular signaling in norm and pathology of the Institute of Molecular Biology. V.A. Engelhardt Institute of Molecular Biology of the Russian Academy of Sciences Denis Demin.

Employees of the National Medical Research Radiological Center of the Russian Ministry of Health(Moscow) and the University of Haifa (Israel) also took part in the work.

The data obtained will be useful in the development of drugs for the treatment of glioblastoma, targeting the studied RNA. In the future, the research team plans to study the role of this molecule in cells of other tumor types, where STAT3 is also associated with resistance to therapy.

Photo: provided by the Engelhardt Institute

The study is of great interest, especially in practical oncology. It is worth noting that the majority of glioblastoma cases are resistant to modern drug treatment, said Igor Utyashev, director of the Clinical Research Department of Medscan Group, leader of the melanoma, skin tumors and sarcomas group at the Hadassah Institute of Oncology.

- Therefore, overcoming the resistance of glioblastoma to chemotherapy can significantly improve the results of treatment of this extremely aggressive tumor, - said the specialist.

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Often, drugs affect either the genes themselves or the products of the protein gene, but it is not always possible to select such targeting drugs that could specifically and precisely act on such targets, said Albert Rizvanov, head of the Center of Excellence "Personalized Medicine" of Kazan (Volga Region) Federal University, corresponding member of the Academy of Sciences of the Republic of Tatarstan.

Photo: provided by the Engelhardt Institute

- And the search for new targets, through which it is possible to influence either the viability of tumor cells or the development of resistance, can open prospects for the development of new classes of drugs, - he said.

However, it is necessary to wait for the results of clinical trials, experts emphasized.

The results of the study, supported by a grant from the Russian Science Foundation (RNF), were published in the journal Gene.