Researchers present a new way of treating cancer

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A team of researchers that includes experts from the International Laboratory of Bioinformatics of the Faculty of Computer Science, HSE University has presented a new way to fight melanoma. The scientists discovered that a form of DNA molecule entering cancer cells is able to induce an immune response similar to the body's response to a virus. As a result, the cells that support tumour growth are killed and the patient begins to respond to anti-cancer therapy again. The results of the study have been published in the Nature.

Scientists from Russia, the USA, China, Australia and Japan have presented a new method of fighting cancer that is hard to treat and, particularly, does not respond to immunotherapy. The new method is based on an alternative structure of DNA molecule — Z-DNA. It represents a double helix twisted to the left, in contrast to the classic and most common form of DNA twisted to the right. 

Z-DNA was discovered back in 1979 but its role and function remain poorly understood. For a long time, the scientific community neglected research in this area. Only in recent years has it been reported that Z-DNA plays an important role in the immune response against viruses. 

Two proteins, ADAR1 and ZBP1, are involved in the formation of Z-DNA in mammals. They are distinguished by the presence of a special structural component, the Zα domain, which binds to Z-DNA. The Zα domain was previously discovered by Professor Alan Herbert, scientific supervisor of the International Laboratory of Bioinformatics. 

Proteins with the Zα domain are not produced in healthy cells; they are activated by interferon in the case of inflammation. ADAR1 suppresses the autoimmune response but ZBP1 activates it and triggers the cell death programme to kill cells infected by the virus. This has been demonstrated earlier in a paper by Professor Balachandran of the Fox Chase Cancer Centre, one of the lead authors of the study. In fact, the play of two proteins, ADAR1 and ZBP1, determines the fate of cancer cells: whether they survive or die.  

ADAR1 and ZBP1 proteins are also produced in fibroblasts, connective tissue cells, when cancer develops. These are healthy skin cells that cancer cells enslave to maintain growth. Cancer cells rely on ADAR1 to suppress the tumour-killing processes. 

While studying a new anti-cancer drug from the curaxin group, researchers discovered an interesting feature of the molecule CBL0137. It turned out that this substance is able to cause massive Z-DNA formation and directly trigger cancer cell death through the activation of the ZBP1 protein, regardless of ADAR1.

The tests were conducted on mice with melanoma. Scientists injected a drug containing the molecule CBL0137 directly into the tumour. This induced an immune response, resulting in the death of fibroblasts that support tumour growth and the cancer cells reacting to immunotherapy again. It did not matter which mutation originally triggered the cancer.

Maria Poptsova

This research is an example of a perfect collaboration between experimental and computer teams. Our American colleagues generated big data from high-tech experiments, we produced bioinformatics analysis on this data. Intelligent data analysis carried out in our laboratory significantly reduced the time and cost of the experimental part of the work. As a result of this win-win strategy, everyone involved in the project benefited.

The entire computational part of the work was done by the researchers of the International Laboratory of Bioinformatics (HSE University), headed by Maria Poptsova. The bioinformatics analysis was carried out by Alexander Fedorov, a junior researcher in the laboratory. An AI system based on deep learning algorithms for predicting the location of the right parts of the genome was created by Nazar Beknazarov, a doctoral student  and a teacher at the Faculty of Computer Science.

From the viewpoint of basic science, this work is an important step towards understanding the role of alternative DNA structures, such as Z-DNA, in the human body. Research in this area is making it possible to find new, sometimes surprising, ways of treating serious diseases that are genetic in nature. It usually takes many years between the discovery of a drug and its release on the market, but in this case, the drug with CBL0137 has already undergone clinical safety studies, which means that it could be used in clinical practice very soon.