A team of researchers from five Swedish universities have identified a new way of treating cancer.
The concept is presented in the journal Nature and is based on inhibiting a specific enzyme called MTH1, which cancer cells, unlike normal cells, require for survival. Without this enzyme, oxidized nucleotides are incorporated into DNA, resulting in lethal DNA double-strand breaks in cancer cells. The research group at Stockholm University has determined the structure of MTH1 and made detailed structural studies important for the development of efficient inhibitors targeting MTH1.
In the current study, the researchers present a general enzymatic activity that all cancers tested rely on and that seems to be independent of the genetic changes found in specific cancers. The research team shows that all the investigated cancer tumours need the MTH1 enzyme to survive. In this way, cancer cells differ from normal cells, which do not need this enzyme.
“The concept is built on the fact that cancer cells have an altered metabolism, resulting in oxidation of nucleotide building blocks. MTH1 sanitises the oxidized building blocks, preventing the oxidative stress from being incorporated into DNA and becoming DNA damage. This allows replication in cancer cells so they can divide and multiply. With an MTH1 inhibitor, the enzyme is blocked and damaged nucleotides enter DNA, causing damage and killing cancer cells. Normal cells do not need MTH1 as they have regulated metabolism preventing damage of nucleotide building blocks. Finding a general enzymatic activity required only for cancer cells to survive opens up a whole new way of treating cancer,” says Thomas Helleday, professor at Karolinska Institutet, who leads the study.
To take the treatment concept towards a clinical application, the scientists have taken a multidisciplinary collaboration strategy with researchers from five Swedish universities. They have produced a potent MTH1 inhibitor that selectively kills cancer cells in the tumours.
Source: Stockholm University