On October 8, 2020 CNIO – Spanish National Cancer Research Centre reported that The CRISPR / Cas9 gene editing tool is one of the most promising approaches to advancing treatments against genetic diseases – including cancer – an area of ​​research in which progress is constantly being made (Press release, CNIO -nish National Cancer Research Centre, OCT 8, 2020, cnio.es/noticias/publicaciones/reprograman-crispr-en-ratones-para-eliminar-celulas-tumorales-sin-afectar-sanas/ [SID1234568223]). Now, the Molecular Cytogenetics Unit headed by Sandra Rodríguez-Perales at the National Center for Oncological Research (CNIO) has taken another step to be able to effectively apply this technology to eliminate so-called fusion genes , which in the future could open the doors to the development of cancer therapies that specifically eliminate tumors without affecting healthy cells. The work is published inNature Communications .

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Fusion genes are the aberrant result of the erroneous union of DNA fragments that come from two different genes, an alteration that occurs by chance during the process of cell division. If the cell cannot take advantage of the mistake, the carrier cells will die and these genes will be eliminated. But when they confer a proliferative or survival advantage, the carrier cell multiplies and the fusion genes and the proteins that they encode become the initiating event of a cancer. "Many chromosomal rearrangements and the fusion genes they produce are the origin of childhood sarcomas and leukemias," explains Sandra Rodríguez-Perales, co-lead author of the study now published by the CNIO. Also foundin tumors of the prostate, breast, lung or brain, among others: in total, up to 20% of all cancers.

Because they are only present in tumor cells, fusion genes arouse great interest in the scientific community, to turn them into highly specific therapeutic targets, in such a way that they only act on the tumor and do not produce effects in healthy cells.

And here comes the CRISPR technology. Using this technology, researchers can target specific sequences in the genome and, as if they were using molecular scissors , cut and paste DNA fragments and thus modify the genome in a controlled way. In the study carried out by the CNIO team, the researchers have worked with cell lines and mouse models of Ewing’s sarcoma and chronic myeloid leukemia , in which they have managed to eliminate tumor cells by cutting the fusion genes, the beginning of the tumor.

The tumor cell repairs itself… and destroys itself

It is the first time that CRISPR has been successfully applied for the selective removal of fusion genes in tumor cells. Previous strategies of other research teams are based on modifying the junction point of the two genes involved in the fusion to introduce a DNA sequence that induces cell death. The problem is that the introduction of external sequences has proven to be very ineffective in eliminating tumors.

CNIO researchers have used an entirely different approach to induce the tumor cell to self-destruct. "Our strategy has consisted in making two cuts in introns, non-coding regions of the gene, located at both ends of the fusion gene," explains Raúl Torres-Ruiz , co – author of the work. "In this way, the cell, when trying to repair these breaks by itself, will join the cut ends, producing the complete elimination of the fusion gene that is located in the middle." As this gene is essential for its survival, this repair automatically induces the death of the tumor cell .

"In the next steps, we will continue to carry out studies to analyze the safety and efficiency of our approach," continues Rodríguez-Perales. "These steps are essential to know if our approach could be transferred in the future to a potential clinical treatment. Furthermore, to study whether our strategy, which we have already seen to work in Ewing’s sarcoma and chronic myeloid leukemia, is also effective in other types of cancer caused by fusion genes and for which there are currently no effective therapies ", he concludes.

The work has been funded by the Ministry of Science and Innovation, the Carlos III Health Institute, the European Regional Development Fund, the Spanish Association Against Cancer (AECC), the European Research Council, the Generalitat de Catalunya, the Network of Cellular Therapy, FERO, the "la Caixa" Foundation, the Josep Carreras Foundation and the Xarxa de Bancs de Tumors de Catalunya.