A classic boxing move,
the 'one-two punch', could also be effective against cancer: a left
jab knocks cancer cells senseless, quickly followed by a right hook
that knocks them out altogether. Researchers at the Netherlands
Cancer Institute have shown that cancer cells are vulnerable to
this kind of approach. "This is a beautiful, universal principle,
that could be used for all forms of cancer." On October
2nd the researchers publish their results in Nature.
Many combinations of cancer medicines could theoretically work
very well together, but in practice these combinations are too
toxic for the body to withstand. The researcher
René Bernards has devised a possible alternative: the 'one-two
punch', named after the effective combination of two quick
successive punches in boxing.
"The first medicine creates a weakness in the cancer cell and the
second deals a merciless blow to the weakened cell. So while the
two medicines are not given simultaneously, you still get the
benefit of their synergetic effect."
At the Netherlands Cancer Institute, Bernards and his colleagues
investigated whether this worked. As the cancer cell's weak spot
they chose a well-known cell reaction to stress: senescence. Under
stressful circumstances ordinary body cells can put themselves into
a kind of sleep mode. They do so, for instance, if their DNA is
damaged. This is useful, because they then stop proliferating and
the body's own immune system can clear them up.
In the laboratory Bernards and his colleagues found a way to
bring this about in liver cancer cells. This was doubly useful: the
cells stopped proliferating, and they had a vulnerability that
could be exploited, since the researchers also discovered a way to
knock out the 'sleeping' cells. Working with liver cancer cells,
the researchers finally identified a combination of medicines that
had good results in mice (see box). On October 2nd they
publish the results of their experiments in Nature.
Exploiting a weakness
"The great thing about this approach is that it could work for a
wide range of tumour types," says Bernards. "In principle,
senescence can be induced in all kinds of tumours." Provided you
know how, and how you then deal the sleeping cells a death blow.
Bernards recently founded a company, Oncosence, which is entirely
devoted to identifying substances that induce senescence in cancer
cells and other substances that kill these specific cells. The
second 'punch' is essential. "It seems that senescent cancer cells
can actually encourage tumour growth and metastasis if the immune
system, or a therapy, does not remove them."
The idea of the 'one-two punch' arose out of
earlier research in which researchers at the Netherlands Cancer
Institute exploited a weak point in resistant skin cancer cells in
order to destroy them. "The principle of exploiting a weakness was
one we wanted to apply more widely, and we identified senescence as
a universal response that could be used in this way." Having been
awarded a substantial
grant by the European Research Council, the research
group is now searching for different ways to induce senescence in
What did the researchers investigate?
With a large-scale genetic screen the researchers identified a
protein whose inhibition induces senescence in liver cancer cells:
CDC7 kinase. By subjecting senescent cancer cells to a great many
chemical substances, they discovered that the common antidepressant
sertraline could kill the senescent cells. Once they had identified
how the drug had this effect (through the cell's mTOR signal
route), they could start searching for drugs that performed this
even more effectively. In laboratory mice they then combined a
CDC7-inhibitor with an mTOR-inhibitor, both of which are already
used in research and which have been individually tested on cancer
patients. The result: twice as many mice survived in comparison
with those receiving current standard treatment.
Earlier this week it became clear that such smart treatment
combinations that originate in the lab of scientist René Bernards
can be effective in patients.
A clinical trial in bowel cancer patients showed positive
results. Patients with metastatic bowel cancer and a mutation in
the BRAF gene treated with a smart combination of three drugs
survive longer than those who have standard treatment. Read more
about his research
This research was partly funded by the Dutch Cancer Society
through Oncode Institute and by the European Research