A new concept for the treatment of cancer
Crystal structure of human MTH1 in complex with a key inhibitor.
Source: Stockholm University, Prof. Pal Stenmark.
A team of researchers from five Swedish universities has identified a new way to treat cancer. They present their concept in the journal „Nature“. It is based on inhibiting a specific enzyme called MTH1. Cancer cells, unlike normal cells, need MTH1 to survive. Without this enzyme, oxidized nucleotides are incorporated into DNA, resulting in lethal DNA double-strand breaks in the cancer cells. The research group at Stockholm University has determined the structure of MTH1 based on diffraction measurements at HZB´s MX-beamline at BESSY II. These detailed structural studies are important for the development of efficient inhibitors targeting MTH1.
In recent decades, the development of new anticancer agents focused on targeting specific genetic defects in cancer cells. These often are effective initially, but later cause trouble due to emerging rapid resistance. 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 respect, 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,” says Thomas Helleday, professor at Karolinska Institutet, who leads the study: "MTH1 repairs 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.
Original publication:
“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. http://dx.doi.org/10.1038/nature13181.
“Stereospecific targeting of MTH1 by (S)-crizotinib as anticancer strategy”, Kilian V. M. Huber, Eidarus Salah, Branka Radic et al., Nature, online 2 April 2014, doi: 10.1038/nature13194. http://dx.doi.org/10.1038/nature13194
- Alternating currents for alternative computing with magnetsA new study conducted at the University of Vienna, the Max Planck Institute for Intelligent Systems in Stuttgart, and the Helmholtz Centers in Berlin and Dresden takes an important step in the challenge to miniaturize computing devices and to make them more energy-efficient. The work published in the renowned scientific journal Science Advances opens up new possibilities for creating reprogrammable magnonic circuits by exciting spin waves by alternating currents and redirecting these waves on demand. The experiments were carried out at the Maxymus beamline at BESSY II.
- BESSY II: Heterostructures for SpintronicsSpintronic devices work with spin textures caused by quantum-physical interactions. A Spanish-German collaboration has now studied graphene-cobalt-iridium heterostructures at BESSY II. The results show how two desired quantum-physical effects reinforce each other in these heterostructures. This could lead to new spintronic devices based on these materials.
- Green hydrogen: MXenes shows talent as catalyst for oxygen evolutionThe MXene class of materials has many talents. An international team led by HZB chemist Michelle Browne has now demonstrated that MXenes, properly functionalised, are excellent catalysts for the oxygen evolution reaction in electrolytic water splitting. They are more stable and efficient than the best metal oxide catalysts currently available. The team is now extensively characterising these MXene catalysts for water splitting at the Berlin X-ray source BESSY II and Soleil Synchrotron in France.