New general concept for the treatment of cancer

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.

Gad et al., (2014). MTH1 inhibition kills cancer by preventing sanitation of the dNTP pool. Nature, EPub Ahead of Print, doi: 10.1038/nature13181 [Abstract]

Huber et al., (2014). Stereospecific targeting of MTH1 by (S)-crizotinib as anticancer strategy. Nature, EPub Ahead of Print, doi: 10.1038/nature13194 [Abstract]


Higher risk of death from skin cancer among men living alone

There are differences in prognosis in cutaneous malignant melanoma depending on cohabitation status and gender, according to a new study published in the scientific periodical Journal of Clinical Oncology. Single men of all ages are more likely to die of their disease.

Cutaneous malignant melanoma is the most aggressive form of skin cancer. The disease is one of the fastest growing cancers among Caucasian (white) populations and is an escalating health problem even among young individuals. Swedish researchers from Karolinska Institutet and Linköping University have now, for the first time, made a detailed study of the link between the prognosis of cutaneous malignant melanoma and whether the patient lives alone or with a partner, by using the unique data from the Swedish Melanoma Register.

The current study is based on all cutaneous malignant melanomas diagnosed in Sweden between 1990 and 2007. The researchers examined the risk of dying from melanoma among more than 27,000 melanoma patients in relation to their cohabitation status at the time of diagnosis. The analysis adjusted for factors already known to affect the prognosis, such as the characteristics of the tumour, gender, educational level, and body site of the tumour was.

Melanoma of the skin can be cured if the tumour is surgically removed before the cancer cells have spread to other parts of the body. For thin cutaneous malignant melanoma that is detected early, long-term survival is over 90 per cent. However, for patients with advanced disease at the time of diagnosis, the prognosis is much worse. Early detection is essential for a good prognosis

We were able to show that living alone among men is significantly associated with a reduced melanoma-specific survival, partially attributed to a more advanced stage at diagnosis. Our study shows that this applies to men of all ages, regardless of their level of education and place of residence,” says first study author Hanna Eriksson, PhD at the Department of Oncology-Pathology, Karolinska Institutet, also working as an MD at the Karolinska University Hospital.

The researchers also found that older women living alone have a more advanced disease at diagnosis, but for single living women as a group there was no effect on the melanoma-specific prognosis.

This points to a need for targeted interventions for earlier detection of cutaneous malignant melanoma in men and older individuals since this is critical for surviving the disease. By way of example, procedures are needed for skin examinations of these patients in connection with other doctor visits or check-ups,” says Hanna Eriksson.

According to the researchers, one possible explanation, particularly for the men and older women diagnosed with melanoma in later stages, are differences in taking on board information about the disease. But it could also relate to insufficient access to skin examinations.

Eriksson et al., (2014). Later stage at diagnosis and worse survival in cutaneous malignant melanoma among men living alone: A nationwide population-based study from Sweden. J. Clin. Oncol., EPub Ahead of Print, doi: 10.1200/JCO.2013.52.7564 [Abstract]