How to treat neuroblastoma?
The level of expression of a pair of genes will determine the need to prescribe antibody drugs for cancer
XX2 century based on the materials of the MIPT press service.
Bioinformatics from MIPT together with colleagues from the Institute of Bioorganic Chemistry named after M. M. Shemyakin and Yu. A. Ovchinnikov, Sechenov University, the Institute of Biomedical Chemistry named after V. N. Orekhovich, NMIC DGOI. Dmitry Rogachev, Skolkovo Center and Biomedical companies Omicsway, Oncobox and Real Target have developed a method for determining the GD2 ganglioside molecule, which is actively produced in cancer cells and serves as a therapeutic target. The result of the study may increase the effectiveness of cancer therapy with GD2-specific antibodies.
Article by Sorokin et al. RNA Sequencing-Based Identification of Ganglioside GD2-Positive Cancer Phenotype is published in the journal Biomedicines.
Ganglioside GD2 is a complex non–protein molecule present in large quantities on the surface of many cancer cells. Since healthy cells produce it in very limited quantities, GD2 is well suited for targeted immunotherapy. The use of monoclonal antibodies that bind specifically to this substance has entered clinical practice for the treatment of certain types of cancer.
The GD2 content on the cell surface determines the effectiveness of such immunotherapy, so it is important to learn how to reliably detect this molecule in tumor tissues. The classical method of immunohistochemistry often leads to incorrect results due to the complexity of measurements directly in the samples of fixed tissues that are obtained during biopsy. The analysis of RNA sequencing data turns out to be more convenient and more accurate, so bioinformatics took up the search for a connection between the content of GD2 ganglioside and the work of marker genes.
Since GD2 is produced as a result of a series of sequential biochemical reactions, its content depends on the balance of the enzymes involved in the processes. The activity of the latter is affected by the level of expression of the genes encoding them. That is, according to the expression levels of these genes, it is possible to classify biological samples based on their GD2 content – to determine their GD2 phenotype.
To understand which genes are most associated with the GD2 phenotype, the scientists compared the expression levels of genes involved in the biochemical pathway of ganglioside synthesis. A pair of two "nearest" enzymes – catalysts for the synthesis of GD2 itself and its immediate predecessor - were also added to the analysis. Scientists have found out that it is by the expression of these two genes (ST8SIA1 and B4GALNT1) that the GD2 phenotype of a cell can be most accurately predicted. This pair turned out to be a better biomarker than any other or the genes separately. Thus, by calculating the quantitative level of expression of two genes in the patient's cells, we can conclude that GD2-directed therapy is applicable. The result of the study can be used for many types of cancer and will increase the effectiveness of GD2-specific antibody therapy.
"The cost of treatment with GD2-specific antibodies can be hundreds of thousands of dollars, and it helps with neuroblastoma in about a quarter of cases, and often has very strong side effects. It turns out that for most patients such therapy is useless, even harmful, not to mention the costs. To avoid this, it is necessary to introduce new molecular diagnostic approaches. This is the task of our laboratory," he comments Anton Buzdin, Head of Research and Head of the Laboratory of Translational Genomic Bioinformatics at MIPT.
The work was carried out with the support of the Russian Foundation for Basic Research.
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