New general concept for the treatment of cancer
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A team of researchers from five Swedish universities, led by Karolinska Institutet, 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.
To accelerate the development of this treatment principle and to proceed with clinical trials in patients as quickly as possible, the researchers have been working with an open innovation model. Even before publication, they sent out MTH1 inhibitors to a range of research groups worldwide.
In recent decades, the development of new anticancer agents has focused on targeting specific genetic defects in cancer cells. These are often effective initially, but are troubled with rapid resistance emerging. 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 that cancer cells have an altered metabolism, resulting in oxidation of nucleotide building blocks. MTH1 sanitises the oxidized building blocks, preventing the oxidative stress to be 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 kill 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, holder of the Söderberg Professorship at Karolinska Institutet, who heads the study.
To take the treatment concept to 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 that have been surgically removed from skin cancer patients.
In order to select the most promising compounds as drug candidates, they should not only be active in the test tube, but also in the complex environment of the human body. For instance, the molecules must dissolve in the body fluids, be absorbed and be sufficiently stable to be effective in vivo. It is therefore likely that the most active molecule in the test tube will not be the most active molecule in the patient. In the MTH-1 project, the UDOPP profiling platform at Uppsala university screened approximately 300 active compounds in order to select the best possible molecules that would be active in vivo. Depending on the issues, various combinations of assays were used.
“The UDOPP platform is a unique asset for Swedish academic scientists developing new molecular probes and drugs-like molecules. By collaborating with UDOPP, scientists do not have to be lashing in the dark, trying to find out why their test tube molecules do not work in vivo. Instead, they get explanations and guidance on how to advance their projects in the right direction.” says platform director, professor Per Artursson.
A lot of work remains to be done before it is time for clinical trials, which is likely to take at least one or two years, according to Thomas Helleday.
The research team behind the results is concentrated at the Science for Life Laboratory (SciLifeLab), which on behalf of the Swedish Government recently set up a national research platform for drug development. The Swedish universities who participated in the partnership in addition to Karolinska Institutet and the Sahlgrenska Academy/University of Gothenburg are Uppsala University, Linköping University and Stockholm University. Collaboration has also been initiated with the research facilities SP Process Development and SweTox, which was created after the closure of AstraZeneca in Södertälje. The research was primarily funded by the Torsten Söderberg and Ragnar Söderberg Foundations and the Knut and Alice Wallenberg Foundation.
“MTH1 inhibition kills cancer by preventing sanitation of the dNTP pool”, Helge Gad, Tobias Koolmeister, Ann-Sofie Jemth et al., Nature, online 2 April 2014, doi: 10.1038/nature13181.
Watch a video about the project on YouTube.
More information about UDOPP.
Linda Koffmar