Scientists Propose New Way to Fight Cancer
An international collaboration of scientists, including researchers from the International Laboratory of Bioinformatics of the HSE Faculty of Computer Science, have discovered a promising new approach to killing hard-to-treat melanoma. The team has found that an alternative form of the DNA molecule can induce an immune response in tumours—similar to the body's response to a virus— that causes the death of cells that support tumour growth. As a result, the patient becomes more responsive to cancer therapy. The results of the study have been published in Nature.
Scientists from Russia, the US, China, Australia and Japan have presented a new approach to targeting cancers that are resistant to current immunotherapies. The approach exploits an alternative DNA structure called Z-DNA, a double helix that twists to the left, as opposed to the more common form of DNA with a right-handed twist.
Although Z-DNA was discovered back in 1979, its role and functions are not yet well understood because for a long time, the topic received little attention in the scientific community. Only recently was it reported that Z-DNA plays an important role in regulating the immune response to viral infections.
The response involves two proteins, ADAR1 and ZBP1, that specifically recognize Z-DNA. They do so through a Zα domain that binds to the Z-DNA structure. The Zα domain was originally discovered by Professor Alan Herbert, Scientific Supervisor of the HSE International Laboratory of Bioinformatics.
Proteins with the Zα domain are not usually present in healthy cells, but are induced by interferon during inflammation. ADAR1 turns off the autoimmune response, while ZBP1 turns on a cell death programme that kills virally infected cells. This was previously shown by Professor Balachandran of the Fox Chase Cancer Centre, one of the lead authors of this study. The interactions between ADAR1 and ZBP1 determine whether a tumour cell lives or dies.
The ADAR1 and ZBP1 proteins are also expressed in normal connective tissue cells called fibroblasts that cancer cells force to support their growth. Tumours rely on ADAR1 to suppress cell death pathways that would otherwise kill the tumour.
By studying CBL0137, a candidate anti-cancer drug of the curaxin family, the researchers discovered its ability to induce Z-DNA and to activate tumour cell death by ZBP1, bypassing suppression by ADAR1.
Experiments were carried out on mice with melanoma. The researchers injected a drug containing the CBL0137 molecule directly into the tumour. This triggered an immune response that killed the fibroblasts supporting tumour growth, causing cancer cells to respond to immunotherapy again, regardless of which mutation caused the cancer in the first place.
Maria Poptsova, Head of the HSE University International Laboratory of Bioinformatics
'This study has been an example of ideal collaboration between experimental and computer groups. Our US colleagues generated big data from high-tech experiments, and we performed bioinformatic analysis on that data. Data mining carried out at our laboratory made it possible to reduce the time and cost of the experimental work. This was a win-win strategy that benefitted all participants of the project.'
The computational part of the study was carried out under Poptsova's supervision by the laboratory’s researchers. Alexander Fedorov, Junior Research Fellow at the laboratory, performed the bioinformatic analysis. Nazar Beknazarov, doctoral student and lecturer at the Faculty of Computer Science, was responsible for the creation of a deep-learning-based AI system for predicting the location of target genome segments.
From a fundamental science perspective, this study marks an important step towards a better understanding of the role of alternative DNA structures such as Z-DNA in the human body. Research in this area can contribute to discovering novel and sometimes unexpected approaches to treating serious diseases of a genetic origin. It usually takes years between the discovery of a drug and its deployment in the market, but in case of CBL0137, clinical trials to assess its safety have been completed, which means that it will soon be available to patients.