The researchers focused on an enzyme, MTH1, which cancer cells – unlike normal cells – require for cell division. If this enzyme is inhibited, damaged building blocks – nucleotides – will be incorporated into the tumour’s DNA, ultimately killing it.
This breakthrough is the work of researchers from five Swedish universities. Representing Linköping University is Svante Vikingsson (left), from the Division of Drug Research. His role in the project was to analyse cancer cell samples where the MTH1 enzyme was blocked. With a customised mass spectrometer he was able to measure the number of damaged building blocks that had been incorporated into the tumour cells’ DNA.
For Dr Vikingsson, being part of such a high-profile project is a great experience.
“It’s a top-quality international environment, bringing together many different areas of expertise,” says Dr Vikingsson, an analytical chemist, specialising in mass spectrometry.
The study was headed by Thomas Helleday, Torsten and Ragnar Söderberg Professor of Translational Medicine and Chair in Chemical Biology at Karolinska Institutet. Prof Helleday’s aim is now to advance the project to clinical trials with patients as quickly as possible.
“To this end, we sent out an enzyme inhibitor for testing to research groups worldwide – even prior to publication of the article.”
One of these testers was Roger Olofsson Bagge, surgeon at Sahlgrenska Hospital in Gothenburg.
“We were extremely happy when we observed that the tumour from one of my melanoma patients, which had developed a resistance to the previous treatment, responded excellently to this treatment. It’s rare to witness such a breakthrough.”
In recent decades the development of new cancer drugs has focused on targeting specific genetic defects in cancer cells. These drugs can be effective, but one problem is that the cancer becomes resistant. In the study published in Nature, the researchers present a general enzymatic activity that appears in all cancers and that appears to be independent of the genetic changes found in specific cancers. The researchers show 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 at all.
“The background is that cancer cells have an altered metabolism, resulting in damage to more DNA building blocks. MTH1 sanitises the damaged building blocks, and prevents them from being incorporated into the DNA and causing cell death. It also allows the cancer cells to divide. Normal cells do not need MTH1, because their DNA building blocks are intact. This general enzymatic activity in cancer cells paves the way for a whole new method for treating cancer”, says Prof Helleday.
The research was funded primarily by the Torsten Söderberg and Ragnar Söderberg Foundations and the Knut and Alice Wallenberg Foundation.Article: MTH1 inhibition kills cancer by preventing sanitation of the dNTP pool, by Helge Gad, Tobias Koolmeister, Ann-Sofie Jemth et al. Nature, online April 2014. doi: 10.1038/nature13181.
Related links
MTH1 the Story (YouTube) https://www.youtube.com/watch?v=NAPYaSQPios
Helleday Laboratory http://www.helleday.org/