Dual drug therapy offers new hope for deadly childhood cancer
12 July 2012
A new drug combination that boosts the effectiveness of a
gene-targeting treatment could offer hope to children with neuroblastoma,
one of the deadliest forms of childhood cancer.
Researchers at The Institute of Cancer Research in London have
found a way to overcome the resistance of cancer cells to a drug
called crizotinib, which recently showed positive early results in
its first trial in children with cancer. The research has been
published in the journal Cancer Cell.
Crizotinib has already been licensed by the US FDA for use in
adult cancers, but early experience suggests tumours eventually stop
responding to treatment, after developing additional mutations in
the ALK gene targeted by the drug.
The study was conducted by The Institute of Cancer Research in
collaboration with the Dana-Farber Cancer Institute and Children’s
Hospital in Boston. In the study, scientists detailed their new
strategy of combining crizotinib with a second class of drugs — mTOR
inhibitors — to knock out the resistance of cancer cells.
Scientists identified the strategy after revealing for the first
time the role played by the ALK cancer-causing gene in driving
neuroblastoma, which accounts for 15 per cent of all the UK’s
childhood cancer deaths.
Neuroblastomas are cancers of the developing nervous system, and
new drug combinations are desperately needed as aggressive forms of
the disease are very difficult to treat with conventional
Senior author Dr Louis Chesler, leader of the neuroblastoma drug
development team at The Institute of Cancer Research and honorary
consultant at The Royal Marsden NHS Foundation Trust, said: “With
the first paediatric clinical trial reporting substantial responses
to crizotinib in patients with ALK driven tumours, we are looking
for ways to increase the effectiveness of ALK inhibitors in general.
We have identified a very promising way to overcome crizotinib
resistance in neuroblastoma, by adding a second drug called an mTOR
inhibitor. Many mTOR inhibitors are already in adult clinical
“We hope that our work will benefit children with neuroblastoma
by increasing the effectiveness of crizotinib. Our study may also
have relevance for adult patients with ALK-driven lung cancer and
lymphoma who develop resistance to crizotinib, because loss of
treatment response in these patients correlates with the development
of point mutations in the tyrosine kinase domain of ALK. In children
with neuroblastoma these point mutations are in fact the most common
primary somatic changes that we see in ALK, so we hope our work with
a paediatric cancer will in this case help to unravel resistance
mechanisms in adult cancer as well.”
Neuroblastoma patients with ALK mutations frequently have
alterations to the MYCN gene, which is closely linked to the
development of aggressive neuroblastoma but is difficult to target
directly with drugs.
The team therefore set out to investigate how a common ALK
mutation, ALKF1174L, and alterations in MYCN interact to drive the
onset of neuroblastomas, and also to attempt to find a way to
overcome resistance to crizotinib.
They found that the ALKF1174L mutation and changes in MYCN cause
more aggressive, crizotinib-resistant neuroblastoma, by turning on
the PI3K/AKT/mTOR pathway. This pathway has been implicated in the
development of neuroblastoma and many adult cancer types, and has
been an intense focus of drug-development in adult cancer.
The team found that combining an mTOR inhibitor with crizotinib
prevented the growth of neuroblastoma by simultaneously inhibiting
MYCN and ALK, overcoming the resistance of these tumours to
treatment with crizotinib alone. As well as delivering a strategy to
overcome crizotinib resistance in general, this work highlights a
treatment approach that may be effective for patients with
aggressive neuroblastoma who carry both genetic changes at
The study received funding from a variety of sources
including The Neuroblastoma Society, Cancer Research UK, Sparks, the
children’s medical research charity and The Rooney Foundation.