Researchers have discovered a mechanism used by some cancers to inactivate cellular senescence and have succeeded in stopping the growth of malignant melanoma using chemical agents to block this mechanism. The study was performed by an international team of researchers from Universitätsmedizin Berlin, the Max Delbrück Center for Molecular Medicine (MDC) and the Berlin Institute of Health (BIH) and published in Cancer Cell.
In healthy cells, cellular senescence prevents mutated cells from turning into tumors using epigenetic tags to co-control how DNA is activated. Cancer has been known to deactivate the tags, but the mechanism for this was previously unknown.
The research team analyzed almost 500 tissue samples taken from melanoma patients and found a significant increase in the production of demethylase enzymes able to stop activation of senescence. Using melanoma cell cultures as well as mice and zebrafish with malignant melanoma, the team genetically modified the activity of the demethylase enzymes. They also used chemical agents to block the enzymes, which proved effective for turning senescence back on and stopping further division. One of the agents is currently undergoing clinical trials for lung and blood cancer.
The treatment also worked in mice transplanted with human tumor tissue. Once senescence was reactivated, immune cells were observed to migrate into the tumor tissue.
The researchers believe combined use of demethylase blockers and targeted immunotherapy could become a highly effective combination treatment for cancers, particularly melanoma as this cancer has responded poorly to chemotherapy thus far.
Image: Melanoma cells under the microscope. Image courtesy of AG Clemens A. Schmitt, MDC/Charité.