Potential new drugs that block a safeguard used by cancer cells
to stay alive in stressful conditions have shown promise against
myeloma, a cancer of white blood cells made in the bone marrow, a
new study reports.
Blocking a signal that triggers cancer’s response to stress using
the new prototype drugs killed myeloma cells in the lab and
slowed tumour growth in mice.
Cancer cells often have to grow under stressful conditions as
they compete for oxygen, nutrients and space during their rapid
growth and division – and also have to withstand stress caused by
overactive cancer genes.
Scientists at The Institute of Cancer Research, London, believe
that targeting the cell’s stress response could be one way of
treating myeloma, and potentially other cancers, more
effectively.
Their new study was largely funded by Cancer Research UK, and is
published today (Thursday) in the journal Clinical Cancer
Research.
HSF1 is a molecular switch that regulates the levels of hundreds
of proteins involved in a cell’s response to stress, and is
super-activated in many cancer types.
The molecule also plays a role in regulating the amount of
proteins in cells, making it an especially promising target for
myeloma, in which cancer cells in the bone marrow produce an
abnormally large number of antibodies.
A team at The Institute of Cancer Research (ICR) – a research
institute and a charity – analysed genetic information from more
than 250 people with myeloma.
They found that those people whose cancers had high activity of
the HSF1 gene had poorer survival than those whose cancers had
low activity – suggesting that the stress signal may play an
important role in myeloma.
Next, the researchers showed that when HSF1 was genetically
depleted in myeloma cells in the lab, those cells died – showing
that HSF1 is indeed important for their survival.
The researchers then treated myeloma cells with two prototype
drugs designed to block the HSF1 pathway – CCT251236, which was
discovered at the ICR, and another called KRIBB11. They found
that both inhibitors killed a substantial proportion of human
myeloma cells in the lab.
When given in combination with an existing myeloma drug,
bortezomib, both HSF1 inhibitors enhanced the drug’s effect.
In mice treated with CCT251236 or KRIBB11, myeloma tumour growth
was significantly slowed compared with animals that did not
receive any treatment.
Both HSF1 inhibitors also caused some cell death in healthy bone
marrow stem cells and white blood cells, but to a much lesser
extent than in myeloma cells.
The researchers now plan to carry out clinical studies to look
into the possible benefits of an HSF1 inhibitor in people, and to
further investigate the benefits of combination therapy with
bortezomib.
Study co-leader Professor Paul Workman, Chief Executive of The
Institute of Cancer Research, London, said:
“We found that prototype drugs that block a major signal that
triggers cells’ response to stress could be effective against the
bone marrow cancer myeloma. The inhibitors we tested killed
myeloma cells in the lab and blocked the growth of human myeloma
tumours in mice.
“We hope that HSF1 pathway inhibitors could offer a potential new
and much needed way to treat myeloma. The next stage will be to
start testing the new treatment approach in patients in
early-phase clinical trials.
“If we’re going to deliver step-change improvements for cancer
patients, we need to find brand new ways of attacking cancers.
Blocking cancer’s ability to cope with stress is one such
innovative idea, and our study shows that it offers real promise.
I’m excited to see this new approach to treatment assessed in
cancer patients as soon as possible.”
Professor Karen Vousden, Cancer Research UK’s Chief Scientist,
said:
“This study’s identification of a new way to kill myeloma cells
is a step towards improving the outlook for people with this
cancer. While there has been some progress, survival from this
disease still lags behind many other cancers. But before this can
be turned into reality, we will now need to see if this approach
could work in people.”
