An international research team has succeeded in stopping the growth of malignant melanoma by reactivating a protective mechanism that prevents tumor cells from dividing. The team used chemical agents to block the enzymes responsible for erasing epigenetic marks at the DNA. This discovery has potential for use in future combination therapies.
Cellular senescence - a state in which cells terminally cease to divide - prevents mutated cells from turning into tumors. This natural protective mechanism puts cells into a hibernation-like condition and is controlled by epigenetic tags located on the protein building blocks the DNA is wrapped around. These tags co-control how the genetic information encoded by the DNA is actually used. Cancer cells, however, were now found to deactivate the tags via a mechanism that was hitherto unknown.
An international team of researchers led by Professor Clemens A. Schmitt from Charité - Universitätsmedizin Berlin, the Max Delbrück Center for Molecular Medicine (MDC), and the Berlin Institute of Health (BIH) has now demonstrated that, in cancer cells, these important epigenetic marks are often erased by demethylase enzymes. Genetic or pharmacological inhibition of these enzymes restarts the protective mechanism, explains the team in an article published in the journal Cancer Cell.
Demethylase blockers halt malignant melanoma
The research team conducted its study on almost 500 tissue samples taken from patients with black skin cancer, also known as melanoma. In roughly a third of the samples, researchers found a significant increase in the production of the demethylase enzymes able to stop the protective mechanism.
In melanoma cell cultures as well as mice and zebrafish with malignant melanoma, the researchers genetically modified the activity of these enzymes. They also used chemical agents to target and block them, which caused the cells to fall into the sleep-like state of senescence, thus stopping them to further divide. The experiment was even successful in mice with implanted human melanoma tissue, which is important information for future applications in patients. One of the agents used is currently explored in clinical trials for the treatment of lung and blood cancer.
In their investigation of melanoma samples from mice, the researchers observed that immune cells migrated into the tumor tissue once the senescence process had been reactivated by drugs. These and other important findings would not have been possible without using animal models.
Senescence keeps cancer cells in hibernation
Together with programmed cell death, cellular senescence is one of the body's most important lines of defense against cancer. This protective mechanism epigenetically silences genes that regulate cell division. Methyltransferase enzymes mark histone proteins - the "spools" around which DNA is wrapped. These marks deactivate the section of DNA that is next to the histone. Clemens Schmitt and his team investigated two different demethylase enzymes that are able to counteract this process. Their ability to "erase" these histone marks makes the enzymes crucial for controlling and disabling senescence.
Potential seen for combination therapies
Cellular senescence is an important and welcome avenue for cancer therapies due to its ability to prevent the further growth of tumors. But its functions are not limited to blocking cancer, as Schmitt's research team recently reported in the scientific journal Nature.
Clemens Schmitt believes the immigration of immune cells into the tumor that was observed in the senescence mechanism holds great potential for a new type of combination therapy. "We think the combined use of demethylase blockers and targeted immunotherapy might be extremely effective," reports the clinical oncologist and researcher, who is Vice Director of the Division of Hematology, Oncology and Tumor Immunology in Charité's Medical Department.
These findings are particularly promising for the treatment of melanoma, as this cancer responds poorly to chemotherapy and is better combated with the help of new immunotherapies. Schmitt and his colleagues now want to see how well immunotherapy and senescence-inducing therapy can be combined in clinical trials.
The study was supported by the German Research Foundation (Deutsche Forschungsgemeinschaft), the German Cancer Aid (Deutsche Krebshilfe) and the German Cancer Consortium (Deutsches Konsortium für Translationale Krebsforschung). Scientists from the Harvard Medical School in Boston, the Netherlands Cancer Institute in Amsterdam, the Weizmann Institute of Science near Tel Aviv, and the Imperial College in London collaborated in this work.
Yong Yu et al. (2018): "Targeting the Senescence-Overriding Cooperative Activity of Structurally Unrelated H3K9 Demethylases in Melanoma." Cancer Cell 33. doi:10.1016/j.ccell.2018.01.002
The Max Delbrück Center for Molecular Medicine (MDC)
The Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) was founded in Berlin in 1992. It is named for the German-American physicist Max Delbrück, who was awarded the 1969 Nobel Prize in Physiology and Medicine. The MDC's mission is to study molecular mechanisms in order to understand the origins of disease and thus be able to diagnose, prevent and fight it better and more effectively. In these efforts the MDC cooperates with the Charité - Universitätsmedizin Berlin and the Berlin Institute of Health (BIH) as well as with national partners such as the German Center for Cardiovascular Research and numerous international research institutions. More than 1,600 staff and guests from nearly 60 countries work at the MDC, just under 1,300 of them in scientific research. The MDC is funded by the German Federal Ministry of Education and Research (90 percent) and the State of Berlin (10 percent), and is a member of the Helmholtz Association of German Research Centers.
About Berlin Institute of Health (BIH)
The Berlin Institute of Health (BIH) is a biomedical research institution focusing on translational research and precision medicine. BIH is dedicated to improving the prediction in progressive diseases and developing new medicinal products for advanced therapies in order to improve patients' quality of life. The institute is committed to providing excellent research solutions and innovation enabling value-based, personalized healthcare. Charité - Universitätsmedizin Berlin and Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) are independent, member entities within BIH.
About Charité - Universitätsmedizin Berlin
With a total of 3,011 beds, Charité - Universitätsmedizin Berlin is one of the largest university hospitals in Europe. Charité spans 4 campuses and comprises approximately 100 Departments and Institutes. Every year, Charité treats more than 146,000 outpatient and more than 694,000 inpatient cases. With approximately 17,100 staff employed across the Charité group of companies, Charité is one of the largest employers in Berlin. In 2016, the Charité university hospital recorded a turnover of more than €1.6 billion. The areas of research, teaching, and health care delivery are intricately linked, resulting in a working relationship that is characterized by interdisciplinary cooperation. In 2016, Charité was able to secure more than €153 million in third-party funding, as well as approximately €203 million in state funding for research and teaching. With approximately 7,000 future physicians and dentists currently enrolled in degree courses, Charité is one of the largest medical faculties in Germany.