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New general concept for treatment of cancer
Date:
April 2, 2014
Source:
Karolinska Institutet
Summary:
A
team of researchers from five Swedish universities has identified a new
way of treating cancer. The concept 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 cell.
Dr.
Thomas Helleday of Karolinska Institutet and his colleagues have
identified a new way of treating cancer by inhibiting the enzyme MTH1,
which cancer cells require for survival.
A
team of researchers from five Swedish universities, led by Karolinska
Institutet and the Science for Life Laboratory, 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, we are working
with an open innovation model. Even before publication, we have sent out
MTH1 inhibitors to a range of research groups worldwide," says Thomas
Helleday, holder of the Söderberg Professorship at Karolinska
Institutet, who heads the study.
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," says Thomas Helleday."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,"
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. Dr Roger Olofsson Bagge is a surgeon
at Sahlgrenska University Hospital, and also affiliated with the
Sahlgrenska Academy at the University of Gothenburg:
"When we saw
that the tumour from one of my melanoma patients who has developed
resistance to all the current treatment actually responded very well to
the treatment, we were extremely happy. It's rare that you get to
experience and witness such a breakthrough," he says.
However, 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. In another article published in the same issue of Nature
parts of the Swedish research team, together with collaborators in
Austria and the UK present results showing that even previously
identified substances that kill cancer cells work by inhibiting the MTH1
enzyme, something which has not been realised until now.
"That
existing anticancer agents hit the MTH1 shows that the concept really
works. Now that we understand the mechanism, we can develop very
selective inhibitors," says Thomas Helleday
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