Download Trials of Exherin, prescribed either by itself or with

Institute of Psychiatry, Psychology & Neuroscience
NEW CANCER DRUGS
ACT ON NEURONAL PROTEIN
30
Making a difference
Our researchers helped develop Exherin, a new drug that
aims to help stop the spread of cancer and attack established
tumours which is currently being trialled in the USA.
© Institute of Psychiatry, Psychology & Neuroscience
Exherin interacting with the cancer protein
Exherin is a new drug that aims to help stop the spread
of cancer and attack established tumours. It has been
developed by Adherex Technologies in collaboration
with scientists at the Wolfson Centre for Age-related
Diseases and is currently being trialled in the USA.
Exherin works by stopping the activity of the protein
N-cadherin. This protein supports the development of
healthy cells during all stages of life and has a number of
different roles within the nervous system – for example,
it is involved in the growth of axons, the nerve fibres
that help transmit information between neurons and to
other parts of the body. But it can also help cancer cells
move around the body and survive, and promote the
creation of blood vessels that help tumours grow.
As cancer progresses, cells from a primary tumour can
break off and travel to other places by invading nearby
tissue or via the blood or lymphatic system, to form
secondary tumours. Exherin may therefore help stop
the movement of malignant cells and might also cut off
the blood supply to tumours that have already formed.
‘N-cadherin is found on the surface of many cancer
cells,’ says Professor Pat Doherty, ‘and Exherin may
therefore be useful for the treatment of all sorts of
different cancers. This is a promising new cancer drug.’
The research team, led by Professor Doherty and
including Dr Emma Williams and Dr Gareth Williams,
developed laboratory procedures to measure the activity
of N-cadherin and to screen and identify compounds
that could block its function.
They showed that mimetic peptides – small chains
of amino acids that mimic the activity of important
constituent parts of N-cadherin – could impede the
action of the protein.
‘Exherin is one of the simplest of these peptides
composed of only three amino acids,’ says Professor
Doherty.
The team worked with researchers at McGill
University in Montreal, Canada, who launched
Adherex Technologies to manage the development
of the new drug.
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Trials of Exherin, prescribed either by itself or with
traditional chemotherapy, have to date shown the
compound to be safe, well-tolerated and to have some
benefit for patients who have melanoma or a solid tumour.
Melanoma begins in melanocytes, the cells that produce
the pigment melanin that colours skin, hair and eyes.
The most common form of melanoma is a cancer of
the skin. Once it spreads to other parts of the body,
metastatic melanoma is currently very difficult to treat.
Patients in the USA who have secondary pancreatic
and biliary tract cancers are continuing to help test the
safety of Exherin in a current trial sponsored by the
University of Nebraska.
As a result of the work carried out by the team and
their collaborators, researchers around the world are
now investigating the development of drugs that affect
the action of N-cadherin and other proteins from the
same family, says Professor Doherty.
‘The demonstration that N-cadherin peptides
can be used to block its function has opened up new
opportunities for drug development,’ he says. ‘We have
helped put N-cadherin peptides on the map as a new
class of biopharmaceuticals to target cancer.’
Research led by Professor Pat Doherty, Dr Emma Williams
& Dr Gareth Williams
REFERENCES
• Yarom N et al. Phase I clinical trial of Exherin (ADH-1) in patients with
advanced solid tumors. Curr Clin Pharmacol, 2013; 8(1): 81-8
• Lammens T et al. N-cadherin in neuroblastoma disease: expression and
clinical significance. PLoS One, 2012; 7(2): e31206
• Beasley GM et al. Prospective multicenter phase II trial of systemic ADH-1
in combination with melphalan via isolated limb infusion in patients with
advanced extremity melanoma. J Clin Oncol, 2011; 29(9): 1210-15
• Beasley GM et al. A phase 1 study of systemic ADH-1 in combination with
melphalan via isolated limb infusion in patients with locally advanced intransit malignant melanoma. Cancer, 2009; 115(20): 4766-74
• Perotti A et al. Clinical and pharmacological phase I evaluation of Exherin
(ADH-1), a selective anti-N-cadherin peptide in patients with N-cadherinexpressing solid tumours. Ann Oncol, 2009; 20(4): 741-5
• Skaper SD et al. A dimeric version of the short N-cadherin binding motif
HAVDI promotes neuronal cell survival by activating an N-cadherin/
fibroblast growth factor receptor signalling cascade. Mollecular and Cellular
Neuroscience, 2004; 26: 17-23
• Williams G et al. Dimeric versions of two short N-cadherin binding motifs
(HAVDI and INPISGQ) function as N-cadherin agonists. The Journal of
Biological Chemistry, 2002; 277: 4361-67
• Williams EJ et al. INP, a novel N-cadherin antagonist targeted to the amino
acids that flank the HAV motif. Molecular and Cellular Neuroscience, 2000;
15(5): 456-64
• Williams E et al.A novel family of cyclic peptide antagonists suggests that
N-cadherin specificity is determined by amino acids that flank the HAV motif.
The Journal of Biological Chemistry, 2000; 275: 4007-4012
• Viollet C and Doherty P. CAMs and the FGF receptor: an interacting role in
axonal growth. Cell and Tissue Research, 1997; 290: 451-455
• Williams EJ et al. Activation of the FGF receptor underlies neurite outgrowth
stimulated by L1, NCAM and N-cadherin. Neuron, 1994; 13(3): 583-94
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