Cancer's "Dark Matter"
Oncological diseases in Switzerland occupy the second place among the causes of death. One of them, non–small cell lung cancer (NSCLC), is fatal in most cases and remains largely incurable. Unfortunately, even recently approved therapies can only prolong the life of patients for several months, and only a few survive in the long term. There is a search for effective methods of treatment. Researchers from the University of Bern and Insel Hospital have identified new targets for developing therapies for this type of cancer.
Dark matter of the genome
In search of new targets, they turned to a little-studied class of genes called the "dark matter" of the genome. These are long non-coding RNAs (DNCRNAS) that make up the vast majority of the animal genome. The human genome contains about 20,000 "classical" protein-coding genes and 100,000 dncrnas. The functions of 99% of these genes are unknown.
As the name of long non-coding RNAs implies, they do not encode proteins. As in the case of matrix RNA, instructions for the construction of dncRNA are contained in the DNA of the cell.
The new tool identifies potential targets
To study the role of dncRNA in NSCLC, the researchers analyzed publicly available datasets to determine which non-coding chains are present in this disease. As a result, a list of more than 800 DNCRNAS was obtained, the importance of which the researchers wanted to study. They then developed a screening system that prevents the formation of certain DNCRNAS by removing part of the corresponding instructions from the DNA.
Using this screening system and two NSCLC cell lines obtained from patients, the researchers assessed how inhibition of selected DNCRNAS affects proliferation, metastasis formation and resistance to cancer cell therapy.
As a result of the analysis, a list of 80 candidate DNCRNAS with a high degree of confidence was obtained, from which the researchers selected several DNCRNAS for subsequent experiments.
Destruction of long RNA by short
For the following experiments, an approach was used that does not work at the DNA level, but targets DNCRNAS after their formation. The researchers used small synthetic RNA antisense oligonucleotides (ASO) that bind to the DNCRNAS they target and lead to their degradation. It should be noted that several ASOS are approved for the treatment of human diseases, but none of them are for the treatment of cancer.
Experiments have shown that the ASO-mediated destruction of most of the selected DNCRNAS inhibited the division of cancer cells in cell culture. It is important to note that the treatment had virtually no effect on healthy lung cells. In a three-dimensional model of NSCLC, which is more closely similar to a tumor than a cell culture, inhibition of one dncRNA using ASO reduced tumor growth by more than half.
Development of therapy for other types of tumors
The group continues its research at the preclinical research stage and is considering the possibility of collaborating with existing companies to develop a drug for the treatment of patients. As for other types of cancer, the new approach should be easily adaptable, it is only necessary to identify the appropriate dncRNA targets.
Article R.Esposito et al. Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities published in the journal Cell Genomics.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on the materials of the University of Bern: Discovering New Cancer Treatments in the "Dark Matter" of the Human Genome.