IScientists at Imperial College London have
developed a new cancer drug which they plan to trial
in multiple myeloma patients by the end of next
year.
In a paper published in the journal Cancer Cell, the
researchers report how the drug, known as DTP3,
kills myeloma cells in laboratory tests in human
cells and mice, without causing any toxic side
effects, which is the main problem with most other
cancer drugs. The new drug works by stopping a key
process that allows cancer cells to multiply..
Micrograph image of a plasma cell tumour. Photo:
Nephron [CC-BY-SA-3.0]
The team have been awarded Biomedical Catalyst
funding from the Medical Research Council (MRC) to
take the drug into a clinical trial in multiple
myeloma patients, scheduled to begin in late 2015.
Multiple myeloma is an incurable cancer of the bone
marrow, which accounts for nearly two per cent of
all cancer deaths.
Professor Guido Franzoso, from the Department of
Medicine at Imperial College London, who led the
research, said: “Lab studies suggest that DTP3 could
have therapeutic benefit for patients with multiple
myeloma and potentially several other types of
cancer, but we will need to confirm this in our
clinical trials, the first of which will start next
year.”
"This discovery could offer a completely new
approach to treating patients with certain cancers,
such as multiple myeloma."
The new drug was developed by studying the
mechanisms that enable cancer cells to outlive their
normal lifespan and carry on multiplying. In the
1990s, a protein called nuclear factor kappa B (NF-kB),
which plays an important role in inflammation, and
the immune and stress response systems, was
discovered to be overactive in many types of cancer,
and responsible for switching off the normal
cellular mechanisms that naturally lead to cell
death. This enables the cancer cells to survive.
The pharmaceutical industry and scientists around
the world have invested heavily in research into
NF-kB inhibitors, but such compounds have not been
successfully developed as therapies because they
also block the many important processes controlled
by NF-kB in healthy cells, causing serious toxic
side effects.
The Imperial researchers took a different approach,
looking for target genes downstream of NF-kB that
might be responsible for its role in cancer
specifically.
By studying cells from multiple myeloma patients,
they identified a protein complex, named
GADD45ß/MKK7, that appeared to play a critical role
in allowing the cancer cells to survive.
Searching for a safe way to target the NF-kB pathway,
they screened over 20,000 molecules and found two
that disrupted the protein complex. Further
refinements led to the experimental drug, DTP3,
which tests showed kills cancer cells very
effectively but appears to have no toxicity to
normal cells at the doses that eradicate the tumours
in mice.
“We had known for many years that NF-kB is very
important for cancer cells, but because it is also
needed by healthy cells, we did not know how to
block it specifically. The discovery that blocking
the GADD45ß/MKK7 segment of the NF-?B pathway with
our DTP3 peptide therapeutic selectively kills
myeloma cells could offer a completely new approach
to treating patients with certain cancers, such as
multiple myeloma,” Professor Franzoso said.
A spinout company, Kesios Therapeutics, was formed
to commercialise DTP3 and other drug candidates
based on Professor Franzoso’s research, with support
from Imperial Innovations, a technology
commercialisation company focused on developing the
most promising UK academic research.
“The significant progress made by Professor Franzoso
in multiple myeloma is one of the many cancers we
believe his signal transduction research could be
applied to. To help develop this ground-breaking
research further, Imperial Innovations created the
spin out Kesios Therapeutics,” explained Dayle Hogg
from the Healthcare Ventures team at Imperial
Innovations.
This research has been funded by the MRC, the US
National Institutes of Health, and Cancer Research
UK.
For more information
L. Tornatore et al. ‘Cancer-selective
targeting of the NF-?B survival pathway with
GADD45ß/MKK7 inhibitors.’
Cancer Cell, 13 October 2014.
DOI:
http://dx.doi.org/10.1016/j.ccr.2014.07.027.
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