A kaleidoscope of random shapes and
colours sharpens into focus on the microscope slide. The pattern is a
magnification of the cells in a piece of tissue from a DIPG tumour, a devastating and untreatable childhood cancer. With
some excitement, researcher Dr Chris Jones explains that his team has now identified a
genetic ‘driver’ for the disease, which for the first time opens up the possibility
of a cure.
DIPG is the most difficult of illnesses, not only for families
affected by it, but also for medics and researchers trying to confront it. The
tumour begins in the brain stem, a region to which delivery of drugs is
extremely difficult and where surgery is impossible; even getting tissue
samples for diagnosis is a challenge.
For all these reasons, drug companies have never shown any
interest in DIPG. Even if a treatment were developed, the costs of research and
development could not be commercially recouped from the small patient
population of this rare childhood disease.
However, it is precisely for all these reasons that the Institute for Cancer Research does take an interest.
‘At the ICR, if an investigator has a relevant biological
question, we have the luxury of being able to follow that where it leads,’
explains Dr Lynley Marshall, a consultant and fellow researcher from the
neighbouring Royal Marsden hospital.
The ICR and Royal Marsden are unique
in the UK in having their own Drug
Discovery Unit, where priorities can be set solely according to patient
need. Such a facility is virtually unheard of in the public sector because of
the complexity and expense of research in the era of molecular medicine.
Pinpointing a molecular ‘target’ and then plucking its nemesis from an endless array of chemical compounds is a formidable
task usually left to the industrial-scale laboratories of the pharmaceutical
industry. Pharma, though, tend to focus on the ‘low hanging fruit’ of the more
common adult cancers, often simply ‘the big four’ - breast, prostate, lung and
bowel. To have a unit at the ICR focusing specifically on the rare childhood
cancers that cause over 500 deaths every year in the UK is, therefore, not so
much a luxury as a crying need.
To find out how new drugs are being
developed at the Marsden, I had come to visit Lynley on the rambling NHS site
where she is based in the leafy commuter belt of Surrey. A random jumble of Victorian
workhouse brickwork and 1960s brutalist boxes, the Royal Marsden gives a
somewhat haphazard impression on arrival; in truth, though, it offers one of
the most tightly organised sets of services for cancer patients in Europe.
Lynley explains that the combination
of world-class hospital and out-patient treatment with the research facilities
of the ICR, all centrally focused on cancer, make this a global leader. Refreshingly,
this is also a place where the needs of adults, children and adolescents are all given appropriate weight.
She is based in the Oak Paediatric and Adolescent
Drug Development Unit at the hospital, where she heads a group dedicated
specifically to children whose tumours have returned or are refractory – difficult to treat. She
explains how a specialist team of this kind can cater to the complex needs of
such families, many of whom may have to travel long distances. The safety and
efficacy of drugs are carefully monitored, but so are the more holistic needs
of families. Care is age-appropriate and provides, where possible,
opportunities for play and learning; menus are devised around food the children
might even want to eat!
The attention to detail, though, is
not just about the welfare of patients but about quality of research. The
staffing in terms of research nurses and data collectors means investigations
can be conducted rigourously and that the Royal Marsden is an institution that
research sponsors are keen to partner with.
She explains how they work in synergy with the Adult Drug Development
Unit, run by Professor Johann De Bono. This is one of the biggest facilities
internationally and leads on many phase 1 and 2 trials. Because of the
frequency of adult cancers, trials are easier to set up, often in just one or
two centres, and easier to fund. Studies for children, however, tend to lag behind and so De Bono’s team share
intelligence with the Paediatric Unit on the best targets and compounds, on
dosage and safety, on combinations of drugs and on developing relationships
with the companies that produce them.
‘It is a real benefit, ‘explains
Lynley, ’to have that expertise and experience in order to decide which drugs
to carry forward for children.’
Ultimately, though, the process
cannot all be completed in-house; the Units for Drug Discovery and Development
Units, sooner or later, have to partner with a commercial company in order to manufacture
a new drug that can be available in a licensed form in the hospital pharmacy.
How to establish such partnerships for childhood illnesses which offer only
small ‘niche markets,’ is a conundrum that researchers like Chris and Lynley
face on a continual basis.
A factor they have in their favour,
though, is the ‘tried and tested’ reputation of the Royal Marsden - for the
skills of its staff, the detail of its data and the quality of its
communication. For many commercial sponsors, the Royal Marsden is the trial
centre of choice.
Is there not something unfair here,
I ask, in resources and expertise being centralised in one site in the
stockbroker belt of southern England?
Lynley explains that up to a third
of their patients are children from beyond the Marsden’s ‘catchment area.’ They
try to encourage partners to open trials in hospitals up and down the country
but she admits Pharma may prefer to work with just one or two centres with
which they are familiar.
A step forward, she explains, is
that five centres in England have now been validated internationally as having
all the resources necessary for sensitive early phase studies. Along with the
Marsden, there is now Birmingham, Newcastle, Manchester and Great Ormond
Street.
‘We try to open up in all five
centres,’ explains Lynley. ‘If there is more than one drug being tested, we
will have some open in one centre, some in another.’
She explains how the landscape for
clinical trials involving children is changing. The day of testing a single
drug with all available patients is coming to a close. Not only did this mean
that the process moved at an elephantine pace but it also failed to account for
differences at a molecular level between individual patients who all may
nominally have the same kind of tumour.
‘What we need to understand is why
some children don’t respond and of those that do, what is it about their tumour
that shows this.’
What she is talking about here is personalised medicine – profiling a
patient’s tumour in as much molecular detail as possible and seeing if anything
is actionable.
‘This is very active in adult
medicine,’ she says. ‘But now we’re trying to take it to the children.’
I relate how my own daughter,
Bethan, responded extremely well to her treatment for Ewing’s Sarcoma and when
she relapsed after not much more than a year, it came as a complete surprise to
her consultant and no-one could explain why it had happened. If she had been
genetically profiled at the outset might what made her different have been
identified?
Lynley explains that the new
national programme, Stratified Medicine Paediatrics,
ideally should profile patients at initial diagnosis so if they do relapse, a
comparison can be made with the primary stage. Given limited funds, though,
focus is on profiling at relapse and restricted to seven high risk malignancies
at diagnosis.
‘When we get a child referred to the
Marsden,’ she explains. ‘I run the tumour on a panel of 72 genes that are
commonly mutated in adult and paediatric cancers. I can then check if there is
an authorised drug or a clinical trial available or access via a compassionate
use programme.
‘In truth, there is a relatively low
frequency with which you will find something truly actionable in paediatrics.
But when you find one, it is of significance and if we can target it, then that
is important.’
National programmes of genetic
profiling are beginning to lock into international trials which can accommodate
a spectrum of molecular targets. E-SMART is a good example of such a study.
The partner charity is in France and the
UK sponsor is in Birmingham. Three different drug companies, Novartis, Astra
Zeneca and BMS, are all taking part.
Rather than testing a single drug,
E-SMART has seven ‘arms’, each offering a different agent or combination of
agents which target contrasting genes. The intention is to offer ‘matches’ to
the broadest number of relevant tumours that have unmet needs. The trial is
also intended to be adaptable so that if a particular arm proves to be
ineffective, a new one can take its place.
This does seem an attractive prospect
but how, I ask, have you been able to get three competing drug companies to
collaborate on the same programme?
The answer, she explains, is partly
political. French politicians have been persuaded to take an interest in
children’s cancers and have exerted pressure on drug companies. More simply,
though, the trial designers have worked hard to make it amenable to multiple
commercial partners.
‘Each arm has been written
separately as a partnership between the investigator and the company. The arms
are not competing against each other to see whether one drug is better than
another; it’s a completely different population of children because a child has
to have a particular mutation to get that particular combination of drugs.
‘None of the company’s get to see
the whole trial; that’s the other important point. The data is monitored by the
academic sponsor, Institut Gustav
Roussy, not by one of the commercial partners.
‘It
has been a good place to start, she says, ‘and things are moving forward - definitely,
no question. The industry is preparing for the change in the European
Regulation. They have paediatric oncologists embedded in their companies, who
are trying to get their voices heard.’
She smiles.
‘It is an exciting time.’
As I return on the train from Surrey into London, I check on my
tablet for some details about DIPG, for I, like most people, know nothing about
it. One footnote in history I find is that the astronaut, Neil Armstrong, had a
daughter, Karen, who died of the illness in the 1960’s. There is an obvious irony
in the fact that in the same decade when Karen’s father was propelled to the
moon, society could not develop the expertise to cure his child’s cancer.
A half century on, little has changed. But if a ‘cancer
moonshot’ is ever to be launched for our kids, I suspect the groundwork is
already being laid in a sprawling
hospital site deep in the Surrey suburbs.
