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UCL CANCER INSTITUTE
ISSUE 3 Summer 2012
OLYMPIC EDITION
Cancer Institute NEWSLETTER
Image: LOCOG/EPA
Later this year our Institute will celebrate its 5th Anniversary. During this time we have seen an enormous expansion, nearly doubling our number of researchers, tripling our total grant income (to
over £87 million) and most importantly, conducting research that is
transforming patient care. In this issue we reflect our achievements
over the past 6 months (including four publications in the New
England Journal of Medicine). Our Institute exemplifies a seamless
integration of basic, translational and clinical cancer research.
Chris Boshoff, Director
Contents
Introduction...............................1
Transforming Care..................2-4
Cancer Centre News..................5
Research News..........................6
CIRT News.................................7
Cancer Domain.....................8-10
Spotlights.................................11
Commercial News................11-12
Events....................................13
Leading Bone Marrow
Transplantation......................14
Crick News...............................15
Funding..................................16
Contact details:
For further Information regarding
the Institute, or how to Support us,
please contact Anna Roche:
[email protected] or
020 7679 6325
www.ucl.ac.uk/cancer
Lyons Donation
One of the Institute’s key priorities is to develop a Cancer Informatics Centre
to facilitate the collation and analysis of multidimensional data, including that
required to support next generation sequencing, large-scale trials and personalised cancer medicine. Following planning permission granted by Camden Council, the project is now under way, with the Centre to be constructed and installed
on the 6th Floor of the Paul O’Gorman Building; it is hoped that the Centre will
be operational in early 2013. It will accommodate specialist bioinformatics workstations and up to 12 computational scientists. Following an extremely generous
donation from The Lyons Charitable Trust, the Centre will be known as “The Bill
Lyons Informatics Centre.”
Marathon - Nine runners ran the
2012 London Marathon to raise
funds for the UCL Cancer Institute.
These included Catherine King, who
works in the Cancer Institute, Simon
Purnell, who works in the CRUK
and UCL Cancer Trials Centre, and
Martin Meyer, brother of Dr Tim
Meyer from the UCLH/UCL Cancer
Clinical Research Facility.
Many thanks to all the runners
for their fundraising efforts, as a result of which over
£20,000 is expected to be raised for the Institute.
NEWS - RESEARCH - EVENTS
Transforming care
UCL Cancer Institute Scientists Publish Landmark Gene Therapy Trial
Research led by Professor Amit Nathwani, published in the New England
Journal of Medicine shows remarkably encouraging results of patients treated
with Haemophilia B (factor IX deficiency) with gene therapy.
Hemophilia is due to deficiency in a coagulation factor and results in a bleeding disorder that often involves joints and muscles. The most common types
are hemophilia A and B, which are due to deficiencies of factors VIII and IX,
respectively, and show X-linked inheritance. Hemophilia B is due to deficiency
of coagulation factor IX (FIX). The first reported case of hemophilia due to FIX
deficiency was in 1952 and was called “Christmas disease” after the patient,
a 10-year-old boy named Stephen Christmas.
Dr. Amit Nathwani and colleagues from UCL, St. Jude Children’s Research
Hospital and other international collaborators report on a phase II trial, in
which six patients with severe hemophilia B were treated with a single administration of an adeno-associated viral (AAV) vector carrying the factor IX gene.
AAV is a small (4.8 kb), nonpathogenic, single-stranded DNA virus from the
parvovirus family. The vector was generated by replacing the coding sequence for the cap and rep genes of the virus with a liver-specific promoter
and the FIX coding sequence. The vector was packaged in cells that express
cap and rep from a different piece of DNA that does not enter viral particles,
thus generating a replication-incompetent vector that cannot propagate after
gene transfer. Preclinical studies had shown that AAV vectors could be expressed from liver in large animals for at least 10 years. In this study, patients
were treated with an AAV vector that used the capsid protein from serotype
8 (AAV8). Two patients received 2×1011 viral particles per kilogram of body
weight and achieved about 1% of normal FIX activity, two patients received
a threefold higher dose and achieved about 2.5% of normal activity, and two
patients received a 10-fold higher dose and achieved about 7% of normal activity. Expression has been seen for over 6 months in all patients, and prophylactic use of factor concentrate has either been eliminated or reduced.
FIX
In one patient in this AAV8 trial, alanine aminotransferase
levels were found to be about five times the upper limit of
normal at 2 months after gene therapy, and there was in
vitro evidence of cytotoxic T lymphocytes (CTLs) that reacted with epitopes of the AAV8 capsid protein. Prednisolone therapy resulted in normalization of the liver enzyme
level within a month, and FIX expression at 6 months was
3% of normal, which was 30% of the peak FIX activity
seen shortly after gene therapy.
7
6
hFIX:C
(IU/dL)
5
4
3
2
1
0
0
20
40
60
80
Weeks after vector infusion
Expression has remained stable
at around 2% for over two years.
100
In summary, this gene therapy trial with an AAV8 vector
for hemophilia B is the first to achieve long-term expression of a blood protein at therapeutically relevant levels.
If further studies determine that this approach is safe,
it may replace the cumbersome and expensive protein
therapy currently used for patients with hemophilia B.
This technology may soon translate into applications for
other disorders, such as lysosomal storage diseases,
alpha1-anti-trypsin deficiency, and hyperlipidemias.
Key Reference:
Adenovirus-associated virus vector-mediated gene transfer in hemophilia B. Nathwani AC, Tuddenham EG, Rangarajan S, Rosales C, McIntosh J, Linch DC, Chowdary P, Riddell A, Pie AJ, Harrington C, O’Beirne J, Smith K, Pasi J, Glader B, Rustagi P, Ng
CY, Kay MA, Zhou J, Spence Y, Morton CL, Allay J, Coleman J, Sleep S, Cunningham JM, Srivastava D, Basner-Tschakarjan E,
Mingozzi F, High KA, Gray JT, Reiss UM, Nienhuis AW, Davidoff AM. New Engl J Med. (2011) 365(25), 2357-65.
2
Transforming care
DNA Analysis Shows Huge Genetic Diversity in Tumours
Professor Charles Swanton, based at the UCL Cancer Institute and Cancer Research UK’s London Research Institute has shown that taking a sample from just one part of a tumour may not give a full picture of its ‘genetic landscape’. He comments “We’ve known for some time that tumours are a ‘patchwork’ of faults, but this is the first time
we’ve been able to use cutting-edge genome sequencing technology to map out the genetic landscape of a tumour in
such exquisite detail.”
The study is published in the New England Journal of Medicine, 8th March 2012, and shows the first ever genome-wide analysis of the genetic variation between different regions of the same tumour using kidney cancer
samples. They found that the majority, around two thirds of gene faults, were not found in other biopsies from the
same tumour. They identified 118 different mutations – 40 of which were ‘ubiquitous mutations’ found in all biopsies,
53 ‘shared mutations’ that were present in most but not all biopsies and 25 ‘private mutations’ that were only detected
in a single biopsy.
By analysing the location of shared mutations in relation to the whole tumour, the Cancer Research UK researchers
were able to trace the origins of particular subtypes of cancer cells back to key driver mutations. This allowed them to
create a ‘map’ of how the pattern of faults within the tumour might have evolved over time.
This work continues the narrative of cancer evolution and follows the milestone publication (Nature 2011) from Professors Mel Greaves (The Institute for Cancer Research) and Tariq Enver (UCL Cancer Institute). They demonstrated
the genetic architecture of acute leukaemia at the single cell level and showed that leukaemia evolved in a branchlike Darwinian pattern of evolution. The new data from Swanton and colleagues confirm that this is also true for solid
cancers, not only for leukaemia.
Overall, these publications help us to understand how cancer evolves over time,
become resistant to therapies, and have
major implications for cancer genomics
and for the targeted therapy of cancer.
This is thought to be Charles Darwin’s first sketch of an evolutionary
tree of life (circa 1837), taken from
his First Notebook on Transmutation
of Species , which is viewable at the
the Museum of Natural History, New
York. It is now thought that cancer
evolve in a similar manner in each
patient, with different genetic clones
representing the various branches.
Key References:
Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. Gerlinger M, Rowan AJ, Horswell S, Larkin
J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, Varela I, Phillimore B, Begum S, McDonald NQ, Butler A, Jones D, Raine K, Latimer C, Santos CR, Nohadani M, Eklund AC, Spencer-Dene B, Clark G, Pickering L, Stamp G, Gore
M, Szallasi Z, Downward J, Futreal PA, Swanton C. N Engl J Med. (2012) 366(10), 883-92.
Genetic variegation of clonal architecture and propagating cells in leukaemia. Anderson K, Lutz C, van Delft FW, Bateman CM,
Guo Y, Colman SM, Kempski H, Moorman AV, Titley I, Swansbury J, Kearney L, Enver T, Greaves M. Nature. (2011) 469(7330),
356-61.
3
Transforming care
Advancing Ovarian Cancer Treatment
Olaparib is a new anti-cancer agent that targets a specific DNA
repair pathway by blocking a PARP (Poly ADP ribose polymerase)
enzyme. Treatment with olaparib produces shrinkage in more than
a third of patients with ovarian cancer who have a defective BRCA
gene. Patients with a mutation in a BRCA gene have a deficiency of DNA repair by homologous recombination, the pathway by
which normal cells repair DNA damage in the presence of a PARP
inhibitor. Deficiency of homologous recombination repair and inhibition of PARP in these tumours results in cell death by ‘synthetic
lethality’. Inherited BRCA mutations are seen in about 15-20 % of
patients with ovarian cancer but homologous recombination deficiency may be present in up to 50 % of high-grade serous ovarian
cancers due to non inherited defects in BRCA genes and other
non-BRCA related mechanisms.
In the New England Journal of Medicine, March 27th 2012 Prof
Jonathan Ledermann at UCL Cancer Institute and international
co-investigators published the results of a trial he led to evaluate
the activity of olaparib, as maintenance therapy in patients with
recurrent high grade serous ovarian cancer. BRCA gene mutations
were known to be present in some patients on the trial. The trial
tested whether olaparib given after the completion of chemotherapy for recurrent disease delayed further progression or recurrence of ovarian cancer.
The trial was conducted by AstraZeneca, the manufacturer of
olaparib and run in 82 sites in 16 countries. 265 patients were
randomly assigned to olaparib maintenance or placebo following
the completion of chemotherapy. There was a highly significant
delay in tumour progression in patients taking olaparib. The median progression-free survival after the end of chemotherapy was
8.4 months compared to 4.8 months (hazard ratio 0.35; 95% CI
0.25–0.49; P<0.00001). Sixty-eight (50%) and 21 (16%) patients,
respectively, remained on olaparib or placebo treatment at data
cut-off.
However, an interim analysis of survival on immature data has
thus far failed to show a survival benefit. It is possible that there
are subgroups of patients who respond better and for longer, and
this is being investigated further. At the time of publication of the
trial 21% of women remain progression-free on olaparib more than
21 months after study closure, compared to 3% who are on placebo. Olaparib is a highly active drug and further investigation of
these data is required to understand how to bring this highly active
drug into more regular clinical use.
Key Reference:
Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. Ledermann J, Harter P, Gourley C, Friedlander M, Vergote
I, Rustin G, Scott C, Meier W, Shapira-Frommer R, Safra T, Matei D,
Macpherson E, Watkins C, Carmichael J, Matulonis U. N Engl J Med.
(2012) 366, 1382-1392.
Trial Transforms Thyroid Cancer
Treatment into Safer and Shorter
Session
A new gold standard for thyroid cancer treatment has been set, reducing radiation doses to
just one third of the current level, according to
research from the Cancer Research UK UCL
Cancer Trials Centre.
Patients currently have surgery to remove the
entire thyroid gland. A few weeks later they take
a capsule containing radioactive iodine that
destroys any remaining healthy thyroid gland
tissue and any potential cancer cells. Improvements in surgery mean more of the thyroid gland
is removed during the operation, leaving fewer
remaining cells to be ‘mopped up’ - so lower radiation doses are adequate and equally effective.
The HiLo trial of 438 patients at hospitals across
the UK, led by Dr Mallick (Newcastle) and Professor Allan Hackshaw (UCL), showed that giving
selected patients a much lower dose of radioactive iodine in a single oral capsule delivers similar
treatment success to the current higher dose destroying all thyroid gland cells remaining after
surgery, with fewer side effects.
The higher doses of radioactive iodine previously
thought necessary meant that patients had to
stay in a hospital isolation unit for at least two
days while the radiation left their bodies, without
physical contact from family and friends. These
high doses could have several side effects – the
more serious of which occur later in life, such as
a permanent dry mouth, and a small chance that
a new cancer will develop. However, patients taking the lower dose capsule can be treated as an
outpatient. The process is easier, quicker (hours,
rather than days), and patients experience fewer
side effects.
The thyroid gland makes and releases hormones. After it is removed patients require
thyroid hormone tablets for the rest of their lives.
Radioactive iodine works best when patients stop
taking thyroid hormone tablets two to four weeks
beforehand, but this leads to side effects such
as lethargy, fatigue and weight gain, reducing
patients’ quality of life and their ability to function
at home and at work.
A secondary finding of the HiLo study is that patients can avoid these symptoms if they continue to take thyroid hormone tablets and are also given an injection of Thyroid Stimulating Hormone (Thyrogen) just before they take the low
dose radioactive iodine.
Key Reference:
Ablation with low-dose radioiodine and thyrotropin alfa in thyroid cancer. Mallick U, Harmer C, Yap B, Wadsley J, Clarke S, Moss L,
Nicol A, Clark PM, Farnell K, McCready R, Smellie J, Franklyn JA, John R, Nutting CM, Newbold K, Lemon C, Gerrard G, Abdel-Hamid A, Hardman J, Macias E, Roques T, Whitaker S, Vijayan R, Alvarez P, Beare S, Forsyth S, Kadalayil L, Hackshaw A. N Engl J
Med. (2012) 366(18), 1674-85.
4
Cancer Centre NEWS
Momentous Occasion as UCH Macmillan Cancer Centre Opens
The University College Hospital Macmillan Cancer
Centre has opened its doors to patients offering the most
advanced service of its kind in the UK.
Patients have been involved in the design of the Centre
and its services, from the light and airy entrance hall
and uplifting colour scheme to the development of a
web-hosted ‘patient portal’ which gives patients more
control over their care.
The Centre will redefine the way patients
are treated, focusing
on all aspects of
their outpatient care.
The close links to the UCL Cancer Institute will give them the opportunity to take
part in leading-edge clinical trials.
The £100 million development has wellbeing, rehabilitation and cancer survivorship at the heart of its philosophy. This will be supported by the very best diagnostic and treatment techniques to improve survival rates.
The Centre has been developed in partnership with Macmillan Cancer Support,
bringing 100 years’ experience of developing innovative, ground-breaking services
which put the needs of patients and families at the heart of cancer care. The Centre is Macmillan’s largest-ever investment of £10 million. It will also see UCLH continuing its long-standing partnerships with the Teenage Cancer Trust and
Hospital Corporation of America
(HCA) International.
Sir Robert Naylor, UCLH chief
executive, said: “The opening of
the Cancer Centre is a significant
development in our ambition to
become a leader in the provision
of cancer care. Quite simply, the
Centre is the realisation of a longterm dream.”
5
Research NEWS
Novel Insight into Stem
Cell Commitment
How stem cells originate specialised cells is central to
understanding embryonic development and adult tissue
maintenance. The Laboratory of Professor Tariq Enver
has recently tackled this issue by focusing on the general
molecular mechanisms guiding the transition from stem
to the first maturing specialised cells, a process known as
lineage commitment.
The Stem Cell Laboratory team analysed the cellular function and molecular composition of hundreds of individual
cells in stem and specialised compartments of mouse
bone marrow and of a bone marrow-derived model cell
line. They observed that cells can commit to a specialised
lineage with relatively underdeveloped and, interestingly,
varied molecular compositions. Also, in the light of previous observations by them and others, they showed that
some of these early molecular events were rehearsed in
stem cells, albeit infrequently and in an isolated fashion.
composition to meet the functions of a mature specialised
cell.
It is possible that, in addition to guaranteeing the production of specialised blood cell types, the co-existence
of alternative molecular routes into lineage commitment
works to ensure exit from the stem cell state and thus
prevents uncontrolled expansion of stem cells. Their study
defines a paradigm of lineage specification against which
other stem cell systems, including cancer formation may
be read.
They suggest that, by chance, some of these priming
events can swiftly and irreversibly move the cells out of
the stem cell state and into lineage specialisation. The
result is a heterogeneous mixture of early committed cells,
which must then develop and coordinate their molecular
Key Reference:
Inferring rules of lineage commitment in
haematopoiesis. Pina C, Fugazza C, Tipping
AJ, Brown J, Soneji S, Teles J, Peterson
C, Enver T. Nature Cell Biol. (2012) 14(3),
287-94.
How to get Loaded with New Histones
A new study from the UCL Cancer Institute discovers
a novel mechanism underlying histone loading in the
central nervous system
The main focus of Professor Paolo Salomoni’s laboratory is on mechanisms underlying central nervous system
(CNS) pathophysiology, in particular brain cancer development. They have recently discovered a novel mechanism regulating epigenetic changes in the CNS.
Modifications of chromatin are believed to contribute to
cancer development. In particular, the process of transformation is known to dramatically alter the chromatin landscape. However, the molecular mechanisms underlying
these modifications and
the regulatory pathways
involved are not fully
understood. They work
on a chromatin-associated factor called DAXX,
which interacts with the
tumour suppressor PML
and has been discovered
to act as chaperone for
the histone variant H3.3.
Loading of this histone
variant has been implicated in chromatin remodeling at transcribed
The image shows two nucleosomes
loci, heterochromatin
depicted as neurons with DNA
wrapped around them. Different color and telomeres. Remarkcodes indicate i) the presence of either
the canonical histone H3 (yellow) or its
variant H3.3 (pink) and ii) the associated changes in epigenetic information
and transcriptome.
6
ably, somatic mutations in the gene encoding H3.3 have
been recently found in paediatric cases of the brain neoplasm glioblastoma multiforme along with components of
its chaperone complex, DAXX and ATRX, which are also
mutated in neuroendocrine tumours of the pancreas. H3.3
is the first histone found mutated in human cancer. Overall, these studies propose a whole new concept whereby
alterations of histone variant loading may contribute to
disease pathogenesis in the CNS. However, we know
very little about the mechanisms underlying deposition of
H3.3 in the CNS and its potential involvement in transcriptional regulation.
Their work shows that DAXX is associated with regulatory
regions of selected genes in the CNS, where it promotes
H3.3 loading upon neuronal activation. DAXX loss not
only affects H3.3 deposition but also impairs transcriptional induction of these genes. Moreover, they have demonstrated that calcineurin-mediated dephosphorylation of
DAXX is a key molecular switch controlling its function.
Overall, these findings implicate the H3.3 chaperone
DAXX in the regulation of calcium-triggered events, thus
revealing a novel mechanism underlying epigenetic
modifications in the CNS. Alterations of DAXX-mediated control of histone loading could be involved in brain
cancer development as well as
the pathogenesis of other CNS
conditions. Exciting times lie
ahead for research in this area.
Key Reference:
Calcium-dependent dephosphorylation of the histone chaperone DAXX regulates H3.3 loading
and transcription upon neuronal activation. Michod D, Bartesaghi S, Khelifi A, Bellodi C, Berliocchi L, Nicotera P, Salomoni P. Neuron. (2012) 74(1), 122-35.
CIRT NEWS
Cure Cancer
@ UCL is a charity
(RCN.1141310) established by Sandra
Hamilton, which is
funding treatment
into new therapies for Non-Hodgkin’s
lymphoma. The research programme
is led by Professor Tariq Enver and
Dr Rajeev Gupta. A number of highly
successful fundraising events have
already been held, including a mass
Zumbathon at Alexandra Palace in
October attended by almost 4,000
Zumba enthusiasts. The first items of
equipment funded by Cure Cancer
@ UCL have already been installed
at the Institute and we would like to
thank Sandra and her Committee for
all their help.
Debbie Fund was set up in memory of Debbie Phillips who died of
cervical cancer in February 2010, funds research to find better treatments for women with cervical cancer. Over £1m had been raised by
the end of 2011, with over £400,000 raised following a very successful
Ball in September 2011 and Debbie Fund’s nomination as one of the
beneficiaries of the city broker ICAP 2011 Charity Day. Helen Jameson,
a close friend of Debbie’s, has recently taken over from Mark Phillips QC
as Chair of the Debbie Fund.
The Debbie Fund antibody project,
led by Professor Kerry Chester and
Dr Tim Meyer, has made tremendous progress and has recently
announced its collaboration with
the Therapeutic Antibody Group at
Medical Research Council Technology to jointly develop new antibodies that bind to cervical cancer
Antibody targeting a toxic
cell-surface targets and which have
warhead to cancer cells.
the potential to be used in new
treatments for cervical cancer. This exciting collaboration is also being
supported by Cancer Research Technology and UCL Business plc, the
technology transfer organisations of Cancer
Research UK and University College London.
Debbie Fund is continuing to raise funds to
build on this amazing start.
Other events planned are the golf
day on June 14th at Sandy Lane golf
course hosted by Steve Ronan and
Nat West bank.
On the 20th June there is an event
sponsored by Bob Blackman PM,
he will show-case the charity at the
House of Commons.
•1st September - A group are aiming
to climb Mount Kilimanjaro;
Interested parties please email:
[email protected]
•7th October – There are 22 runners
for the Hyde Park half Marathon,
places are already sold out, but if you
wish to go on a waiting list, please
email James Green:
[email protected]
More LLR Success
Drs Ronjon Chakraverty and Clare Bennett have recently been awarded
an LLR programme grant of £1.3 million over 5 years. The overall aim
of the programme is to establish internationally competitive pre-clinical
research at UCL that will underpin translational phase I/II studies in
graft-versus-host disease (GVHD) prevention and graft-versus-leukaemia (GVL) enhancement. Current clinical strategies that rely on global
T cell depletion or pharmacological inhibition of T cell function to prevent
GVHD also impair GVL. Thus, there is a need to identify other ‘checkpoints’ that regulate the development of GVHD but do not interfere with
GVL. The Chakraverty and Bennett groups have shown that GVHD
induction is controlled by a ‘licensing’ checkpoint within GVHD-target organs that is regulated by tissue dendritic cells (DC). Thus, a key focus
of the programme will be to determine the mechanism of licensing using
innovative genetic and imaging approaches, with the aim of identifying
novel checkpoints that can be targeted to selectively inhibit GVHD. In
other work, the UCL research team has shown that GVL effector responses are lost over time because effector cells become ‘exhausted’,
an outcome that is driven by recognition of antigen upon radioresistant
cells in the host. Therefore, a second objective will be to identify the molecular mechanisms that lead to this dysfunction of GVL effectors. This
work will afford an opportunity to design new treatments to improve the
integrity and longevity of the GVL response.
Key References:
Langerhans cells regulate cutaneous injury by licensing CD8 effector cells
recruited to the skin. Bennett CL, Fallah-Arani F, Conlan T, Trouillet C, Goold H,
Chorro L, Flutter B, Means TK, Geissmann F, Chakraverty R. Blood. (2011), 117(26), 7063-7069.
An inflammatory checkpoint regulates recruitment of graft-versus-host reactive T cells to peripheral tissues. Chakraverty R, Côté
D, Buchli J, Cotter P, Hsu R, Zhao G, Sachs T, Pitsillides CM, Bronson R, Means T, Lin C, Sykes M. J Exp Med. (2006), 203(8),
2021-2031.
Nonhematopoietic antigen blocks memory programming of alloreactive CD8+ T cells and drives their eventual exhaustion in mouse
models of bone marrow transplantation. Flutter B, Edwards N, Fallah-Arani F, Henderson S, Chai JG, Sivakumaran S, Ghorashian
S, Bennett CL, Freeman GJ, Sykes M, Chakraverty R. J of Clin Investigation. (2010), 120(11), 3855-3868.
7
Cancer Domain
Comprehensive, Seamless Pathways of Care
Across the System
London Cancer, which began
operating on 1 April 2012, brings
together all 12 of the area’s secondary and tertiary care providers
in a formal governance structure,
which also harnesses the expertise
of leading cancer academics and
charities. This new partnership will
focus cancer care on the needs of
the patient in a way that has not
been possible under the current
model of care, which too often delivers a disjointed and fragmented
experience. It will also address the
poorer cancer clinical outcomes in
London, to eliminate the estimated
1000 avoidable deaths from cancer
in the capital every year.
London Cancer clinicians at local
hospitals will work in partnership
with general practitioners and
colleagues from across the system to map out a comprehensive,
seamless clinical pathway for every
patient. Professor Kathy PritchardJones, Chief Medical Officer for
London Cancer states that patients
will be diagnosed efficiently and
have access to the best care and
treatment the system can offer for
treating their particular cancer, no
matter where they live.
A senior clinical director for each of
the eleven cancer pathways (brain/
CNS, breast, colorectal, haematology, HPB, gynaecology, head
and neck, lung, skin, upper GI and
urology) will support providers to
improve access to screening and
diagnostics so that treatment can
begin as soon as possible. The
pathway directors will also drive the
system towards international best
practice so that all patients have
access to the full range of care of a
world-class system.
More detailed information on
London Cancer is available at:
http://www.uclpartners.com/
our-programmes/cancer
8
Linking Nerve Tumours and Nerve Repair
Peripheral nerves connect our tissues to our spinal cord and brain and
consist mostly of neuronal axons, that transmit the electrical signals,
wrapped by Schwann cells, the glial cells of the Peripheral Nervous System (PNS). The major tumour types that arise in this tissue are neurofibromas; they are caused by mutations in the Neurofibromatosis Type 1
gene (NF1). These tumours consist of progenitor-like Schwann cells dissociated from the axons as well as large numbers of inflammatory cells,
which are thought to be important for the development of the tumour. Peripheral nerves are highly regenerative and are
able to repair after injury. As part of this process,
Schwann cells dedifferentiate to progenitor-like
cells that aid in the repair process. In many ways
the neurofibromas resemble the injured state full of proliferating progenitor-like Schwann cells
and inflammatory cells. However, unlike the
wounding situation these tumours do not resolve
and for this reason have been referred to as
“unrepaired wounds”.
Confocal images of
Research carried out by Alison Lloyd’s laborato- cross-sections of sciatic
ry has now identified a pathway downstream of nerve immunostained for
the NF1 gene, the Raf/ERK signaling pathway,
P-ERK (red) and the myelin
which can drive the dedifferentiation of Schwann protein P0 (green) in P0-RafTR tamoxifen-injected mice.
cells in vivo. The group has developed a powerful mouse model in which the Raf/ERK pathway can be regulated in
Schwann cells by a drug and can be activated to mimic the normal injury
signal. Following the activation of Raf in these mice, the Schwann cells
dedifferentiated en masse resulting in demyelination and a severe impairment of motor function. Moreover, the Schwann cells re-entered the cell
cycle and began to produce factors that induced a robust inflammatory
infiltration of the nerve - despite the absence of injury. The phenotype of
demyelination and the inflammatory response was fully reversible after
the drug was removed and the signal switched off. Building on these
findings, they were then able to show that pharmacological inhibition of
this pathway attenuated the
demyelinating response and
inflammatory response following
an injury to the nerve. These
results offer further insights into
the pathways controlling the regenerative potential of peripheral
nerves and how these pathways
can be subverted to form neurofibromas. It is hoped that this will
lead to better therapeutics both
for treatment of nerve disorders
and cancer.
Key Reference:
A central role for the ERK-signalling pathway in controlling Schwann cell plasticity
and peripheral nerve regeneration in vivo. Napoli I, Noon LA, Ribeiro S, Kerai A,
Parrinello S, Rosenberg L, Collins M, Harrisingh M, White IJ, Woodhoo A and
Lloyd AC. Neuron. (2012) 73, 729–742.
Cancer Domain
Hypoxia Signalling, Mitochondria and Cancer Progression
Dr Margaret Ashcroft heads the Centre for Cell Signalling and Molecular Genetics within the Division of Medicine. Her
group has been discovering how tumour cells survive when they experience low oxygen levels (hypoxia). Most solid
tumours contain areas of hypoxia which renders them resistant to many treatments, and usually is associated with
aggressive disease and poor patient survival.
Tumour cells can adapt to the low oxygen microenvironment within a growing tumour mass. They are able to do this in
part, by turning on an oxygen-sensing mechanism involving the transcription factor hypoxia-inducible factor (HIF). Activated HIF upregulates the expression of genes involved in many cellular processes enabling tumour cells to survive,
proliferate and migrate. One process by which activated HIF can increase the oxygen supply to a tumour is by increasing the expression of vascular endothelial growth factor, an angiogenic factor that encourages blood vessels to grow
into the tumour mass from the surrounding tissue. This process is known as angiogenesis. Dr Ashcroft and her group
have identified novel small molecule agents that block cancer progression by turning off HIF. The group’s novel HIF
inhibitors can also be used to improve the anti-tumour effect of current cancer treatments such as radiotherapy.
Many human cancers show increased HIF activity due to increased levels of the HIF-α, the regulatory subunit of HIF.
Dr Ashcroft and her group have been unravelling the mechanisms underlying how HIF-α protein levels are upregulated in tumour cells. In particular, the group have been exploring the interface between mitochondria and how tumour
cells increase levels of HIF-α. Mitochondria are sometimes referred to as the ‘powerhouse’ of the cell. This is because
mitochondria are the organelles within cells that convert oxygen to chemical energy in the form of adenosine triphosphate (ATP). Indeed over a decade ago, mitochondria were shown to be essential for eliciting the cell’s HIF response
to hypoxia. Surprisingly however, since then, the precise molecular mechanisms responsible for how mitochondria
communicate with HIF have remained elusive.
Dr Ashcroft and her group discovered that the human gene CHCHD4 encodes two highly related mitochondrial proteins
that they have named CHCHD4.1 and CHCHD4.2 (Figure). They found that CHCHD4.1 is identical to MIA40, the human homologue of a yeast protein called Mia40. They discovered that CHCHD4.1 (MIA40) regulates the rate at which
a tumour cell consumes oxygen and generates chemical energy. CHCHD4.1 does this by modulating the activity of HIF.
Indeed, when the expression of CHCHD4.1 is knocked down in tumour cells, HIF-α protein stabilization is significantly
decreased and HIF activation is blocked in response to hypoxia, resulting in significantly decreased tumour growth and
angiogenesis in vivo.
CHCHD4.1 (MIA40)
DAPI
Cytochrome c
Merge
The clinical importance of these novel findings is highlighted by the fact that the group also discovered that CHCHD4
expression is increased in a number of different types of
cancers (including breast, pancreatic and glioma), where
increased CHCHD4 expression significantly correlates with
an increase in the expression of HIF/hypoxia-regulated
genes. Furthermore, by studying 251 breast cancer patients,
they found that levels of CHCHD4 were greatest in samples
that came from patients with more aggressive disease and
significantly poorer survival.
These recent discoveries made by Dr Ashcroft and her
group, identify a crucial missing molecular link in how mitochondria interface with the HIF/hypoxia signalling pathway,
and open up a new avenue of research for therapeutic development.
Key references:
CHCHD4.1 (MIA40) is a mitochondrial protein. Immunostaining analysis of HCT116 human colon carcinoma cells
expressing CHCHD4.1 (MIA40) protein. Cells were fixed
and stained for CHCHD4.1 (MIA40) (green) and imaged by
confocal microscopy. The mitochondria were visualized using
an antibody to cytochrome c (red). The nuclei were visualised
using DAPI (blue). Co-localized proteins are shown in yellow
(merge).
Human CHCHD4 mitochondrial proteins regulate cellular oxygen
consumption rate and metabolism and provide a critical role in hypoxia signaling and tumor progression. Yang J, Staples O, Thomas
LW, Briston T, Robson M, Poon E, Simões ML, El-Emir E, Buffa
FM, Ahmed A, Annear NP, Shukla D, Pedley BR, Maxwell PH, Harris AL, Ashcroft M. J Clin Invest. (2012) 122(2), 600-11.
HIF-1α localization with mitochondria: a new role for an old favorite? Briston T, Yang J, Ashcroft M. Cell Cycle. (2011) 10(23),
4170-1.
9
Cancer Domain
Early Lung Cancer Programme
UCL has a rich history in Lung Cancer studies and many national lung cancer trials are run from the Cancer Research
UK and UCL Clinical Trials Centre and the London Lung Cancer Group. This is currently flourishing under the leadership of Professor Ming Lee and has been boosted by the appointment of Dr Martin Forster to develop early phase
studies.
This clinical activity is being matched by laboratory studies in which UCL has a rapidly growing reputation. Dr Sam
Janes was recruited to UCL as an MRC Clinician Scientist in 2005 and in 2010 he became a Wellcome Senior Fellowship in Clinical Science. His work examines two aspects of stem cell biology in relation to lung cancer. First the use of
exogenous (bone marrow-derived) stem cells as vectors to deliver anti-cancer therapies (Figure). This work has led to
the design of a phase I safety study in humans. Second, he examines the key signalling pathways involved in endogenous airway stem cell maintenance and how dysregulation leads to the early stages of cancer development. He has
particular focus on the Wnt and EGFR pathways. His important work has been recognised by a number of international
awards for his research team and the personal award of European Thoracic Oncology Investigator of the Year in 2010.
A key development over the last three years has been the UCLH/UCH Biomedical Research Centre-funded recruitment
of Dr Adam Giangreco from Cambridge. Dr Giangreco has moved from skin biology to lung biology and has recently
secured his own EU New Investigator Fellowship, examining a
novel tumour suppressor gene in the lung. Importantly all the
work in Dr Janes’ group dovetails closely with his clinical interests
in pre-invasive disease. UCLH has the largest cohort in the UK of
patients with pre-invasive disease lesions and runs the CTAAC
funded Lung SEARCH trial (Professor Spiro and Dr George),
screening patients with chronic obstructive pulmonary disease
for early lung cancers. The unique tissue from these patients is
feeding various translational projects.
Key References:
Β-Catenin determines upper airway progenitor cell fate and preinvasive
squamous lung cancer progression by modulating epithelial-mesenchymal transition. Giangreco A, Lu L, Vickers C, Teixeira VH, Groot KR, Butler CR, Ilieva EV, George PJ, Nicholson AG, Sage EK, Watt FM, Janes
SM J Pathol. (2012) 226(4),575-87.
Myd88 deficiency influences murine tracheal epithelial metaplasia and
submucosal gland abundance. Giangreco A, Lu L, Mazzatti DJ, Spencer-Dene B, Nye E, Teixeira VH, Janes SM J Pathol. (2011) 224(2),
190-202.
Human skin aging is associated with reduced expression of the stem
cell markers beta1 integrin and MCSP. Giangreco A, Goldie SJ, Failla V,
Saintigny G, Watt FM. J Invest Dermatol. (2010) 130(2), 604-8.
Mesenchymal Stem Cells (Green) Infiltrating Lung
Cancer cells (Red) After Intravenous Injection.
Antibody Drug Conjugates – A Perfect Synergy
The antibody engineering group has been working closely with the Therapeutic Antibody Group at MRC Technology
(MRCT) to create humanised full IgG antibodies from single chain Fvs generated by Cancer Institute scientists. The
collaboration has been enabled by UCLB and the antibodies are being commercialised in collaboration with Cancer
Research Technology, the technology transfer organisation of Cancer Research UK.
We are delighted to announce that Spirogen Ltd, a UCL spin out company will be working
with the Cancer Institute to develop the antibodies as drug conjugates (ADCs) for targeted
cancer therapy. Spirogen are world leaders in developing potent DNA sequence-targeted
warheads for ADCs. The synergistic combination of Spirogen’s technology with that of the
antibody group is timely. Paul Ehrlich visualized the future of antibodies as “magic bullets”
and pioneered the use of chemotherapy. Yet, in over 100 years of research since their
birth, these two classes of agents largely have been developed independently. Now, after
a century of gestation, ADCs are rapidly becoming the lead agents in the antibody theraAntibody (grey), Linker (blue),
peutic field.
Drug (Red)
Key Reference:
Drug Conjugates – A perfect synergy. Adair JR, Howard PW, Hartley JA, Williams DG and Chester KA Expert Opinion on Biological
Therapy (2012) in press.
10
Commercial News / sPOTLIGHTS
Under an agreement with Spirogen,
Seattle Genetics
Inc has developed
a pyrrolobenzodiazepines (PBD) molecule that
is being evaluated for future clinical-candidate antibody drug conjugates (ADCs). Data reported at
the103rd Annual Meeting of the
American Association for Cancer
Research (AACR) held in Chicago
in April demonstrate that when this
PBD molecule is conjugated to an
anti-CD70 antibody using Seattle
Genetics’ EC-mAb technology, the
resulting ADC possesses potent
antitumor activity in models of renal
cell carcinoma.
Celtic Therapeutics Management
L.L.L.P. a global private equity
firm focused on novel therapeutic
product candidates, is the majority
owner of Spirogen Ltd. It announced
recently a significant commitment
to ADC products, with the launch
of a new Switzerland-based company ADC Therapeutics Sarl, with
certain co-founders of Spirogen.
The company has an initial budget
of $50million. ADC Therapeutics’
development plan will use well-characterized monoclonal antibodies
for conjugation with best-in-class
warhead and linker chemistry. The
warheads are based on the proprietary PBD “payload”
technology developed by Spirogen
and scientists at
UCL.
PolyTherics Ltd announced in
April a research collaboration with
Spirogen to develop novel ADCs for
the treatment of cancer. Under the
collaboration, the two companies
will produce the ADCs using PolyTherics’ proprietary TheraPEGTM
linker technology to site-specifically
conjugate Spirogen’s potent PBD
cytotoxic agents to antibodies and
antibody fragments.
Professor John Hartley
IN THE SPOTLIGHT
UCL Cancer Institute Postgraduate Students
Maha Abdollah
Maha, who has an undergraduate degree in Pharmacy, came
to UCL from Egypt in 2010 to
take the Cancer Institute’s MSc
Cancer programme. She chose
to do the MSc Cancer programme to give her the essential
background, experience and
skills required to pursue a PhD
in cancer research. Following a
Distinction level degree award in
the MSc Cancer programme, she
was successful in securing two
highly competitive UCL scholarships for PhD studies: the UCL Overseas
Research Scholarship and the UCL Global Excellence Scholarship.
Maha’s PhD project, under the guidance of Professor Kerry Chester,
Professor Quentin Pankhurst and Dr Paul Mulholland, is exploring a novel
treatment for glioblastoma, one of the most aggressive brain tumours. She
is investigating the use of magnetic nanoparticles to deliver targeted heat
therapy directly and safely to cancer cells, while preserving normal brain
tissue. This project is particularly important because there is no standard
effective treatment for patients with progressive/relapsed glioblastoma.
Mette Jorgensen
Mette graduated from medical
school in Aarhus, Denmark
and then moved to London to
continue her clinical training in
Paediatric Oncology. She was
awarded a prestigious clinical
PhD Fellowship from the UCL
Cancer Research UK Centre.
Mette’s research is supervised
by Professor Adrienne Flanagan,
Professor Amit Nathwani, and Dr
Jeremy Whelan; it also entails
collaboration with Dr Peter
Campbell of the Wellcome Trust Sanger Institute.
One part of Mette’s research is to quantify the burden of disease in patients
with sarcoma by monitoring tumour-specific genomic rearrangements in
plasma DNA. She aims to develop protocols for the purpose of screening
for somatically acquired rearrangements in the genomes of these sarcomas and in patient plasma. The protocols will then be used for assessing
response to treatment and monitoring for evidence of relapse of disease.
By sequencing a large number of sarcomas, she hopes to discover novel
rearranged sarcoma-related genes, potential biomarkers and treatment
targets.
Another strand of Mette’s project involves developing a novel RNAi gene
therapy approach to a rare cancer, targeting brachyury in Chordoma.
Mette feels that this PhD fellowship offers an amazing opportunity for her to
gain expertise in cancer genetics and gene therapy, allowing her to work at
the forefront of clinical cancer research now and in the future.
11
Commercial News
Strategic Collaboration
with Prometheus
In addition to genomics infrastructure, which is a priority of the UCL
Cancer Institute, there is an increasing need to define the activation
and inhibition of cellular pathways
in both preclinical models testing
new agents and in clinical studies.
We have signed an agreement with
Prometheus (San Diego), a leading Californian therapeutics and
diagnostic laboratory, for a joint
programme which will analyse up
to 2000 samples annually from the
Cancer Institute using the proprietary COPIA technology. The Collaborative Proximity Immunoassay
(COPIA) is a multiplexed protein
microarray platform utilising the formation of a unique immuno-complex
requiring co-localization of two detector-antibodies. COPIA measures
expression and activation of specific
cancer pathways in tissue or blood
samples, allows the selection and
evaluation of developmental drugs
and facilitates real-time molecular
profiling to monitor the effectiveness
of targeted drug therapies. This will
allow cell lines, biopsies and circulating tumour cells to be analysed
for the activation status of over 90
pathways implicated in cancer cell
proliferation and metastasis.
Bringing Nanotechnology to the Clinic
Our commercial collaborations are being expanded by the winning
of an FP7 collaborative award to develop a new medical device for
treatment of glioblastoma.
The work is led by Professor
Kerry Chester. The treatment
will utilise Ferucarbotran® a
superparamagnetic iron oxide
particle (SPION) manufactured by Japanese collaborators Meito Sangyo and already
proven for use in man as an
FDA-approved MRI contrast
agent. SPIONs generate heat
when placed in an alternata] Ferucarbotran is depicted in blue
ing magnetic field and the
containing iron oxide crystals shown
new treatment will exploit this
as brown spheres embedded in a
property using magnetic alterwatery dextran coat. The DARPins
nating current hyperthermia
are linked to the dextran using an
(MACH) technology developed
engineered C-terminal cysteine tag.
by Resonant Circuits Ltd a UK
Relative size: iron oxide crystals ~5
nm, ferucarbotran particle ~ 60 nm;
start-up company supported by
DARPin ~ 3x5 nm
UCLB. The Ferucarbotran®
will be linked to an EGFR1-specific Designed Ankyrin Repeat Protein (DARPin) and targeted
to EGFR-+ve tumour cells. When localisation has been confirmed by
MRI, the particles will be activated by the MACH device to generate
toxic heat within the tumour. Other commercial partners in the project
are German-based companies, Nano-PET Pharma GmbH and TOPASS GmbH who will be developing the conjugation technology and
pre-clinical evaluation studies.
We are working closely with Prometheus to optimise the technology
and to add specific pathways which
may be relevant to novel agents.
The aim is to integrate this pharmacodynamic endpoint with accurate
mutation status in preclinical and
clinical studies to determine functional effects of anticancer therapy.
A launch meeting will take place in
the Cancer Institute in the next few
months following which applications
will be invited for projects involving
this exciting novel technology.
For further details please contact
Daniel Hochhauser:
[email protected]
12
[b] The particles will
be administered into
tumours of patients with
glioblastoma and targeted specifically to the
tumour cells. Localisation of the particles will
be monitored by MRI
[c] After localisation,
the particles will be
activated to generate
toxic heat.
Events
UCL Cancer Research Public Open Day
One hundred members of the local community attended the UCL
Cancer Research Public Open day on Saturday 28th April. The morning session comprised a series of lectures highlighting key areas of
Cancer Research at UCL.
After lunch there were guided tours of the new UCH Macmillan Cancer Centre, the UCLH/UCL Clinical Research Facility and the UCL
Cancer Institute. Visitors had the opportunity to see the new PET-MRI,
the first in the UK, housed in the
UCH Macmillan Cancer Centre and
hear from Anna Barnes, Rowland
Illing and Alison Reed how the new
machine will contribute to improved
diagnosis and treatment. In the UCL
Cancer Institute visitors donned
lab coats and extracted DNA from
strawberries under the direction
of Kerry Chester and her group
while others visited the recombinant protein production facility and
John Hartley’s GCLP laboratory to
understand how novel drugs are developed and tested. Finally, in the
UCH/UCL Cancer Clinical Research
Facility, Kerry Guile and her team
Open day visitor extracting DNA
of nurses gave demonstrations in
from a strawberry
blood taking and sample processing
while Investigators Martin Forster and Michael Flynn described how
the dedicated facility was allowing patients the opportunity to participate in trials of the latest new anti-cancer agents in a purpose built
environment.
Maggie Wilcox of the Independent Cancer Patients Voice commented
‘I thought the level was just right – We all found it extremely enjoyable
as well as interesting’
The organising committee including Tim Meyer, James Lyddiard,
Emma Hainsworth, Masuma Harrison, Sawretse Leslie and Vicky
Tilley and a small army of staff volunteers did an outstanding job,
ensuring the day ran smoothly. We are also grateful to the four patient
members of the committee who provided invaluable initial advice on
the structure and content of the day.
Future Conferences
Cancer and miRNA
Symposium
The 3rd International Symposium
on ‘Cancer, microRNAs, and other
non-coding RNAs’ will be held on the
12th September 2012, Darwin Lecture
Theatre, UCL. Confirmed speakers
include Frank Slack (Yale University),
Joshua Mendell (UT Southwestern
Medical Center, Dallas),
Javier Caceres
(MRC Human Genetics Unit), Andrea
Califano (Columbia University, NY), Eric
Miska (Gurdon Institute, Cambridge),
Ranit Aharonov (Rosetta Genomics, Israel), Judy Lieberman (Harvard University),
Martin Bushell (University of Leicester, UK). Organisers are Dimitris Lagos
(York University) and Chris Boshoff (UCL
Cancer Institute).
Yale UCL Cancer
Conference
UCL and Yale researchers will hold a
joint cancer conference on the 26 and
27th June 2012. Over 20 cancer physicians and scientists from Yale will visit
UCL, and the event will include the 5th
Annual UCL Cancer Institute and 3rd
Annual UCL Cancer Research U.K. Conferences. These events are open to all,
aim to foster interdisciplinary and international collaborations.
For more information please visit:
www.ucl.ac.uk/cancer/conferences
Methylation Workshop Great
Success
An ‘Infinium 450k Methylation Array Workshop’ was
held on the 20th April 2012, organised by Stephan
Beck and Tiffany Morris of the Medical Genomics
Group, UCL Cancer Institute. International speakers
included Rafael Irizarry, Johns Hopkins University;
Wouter den Hollander, Leiden University Medical Centre; Juan Sandoval, Bellvitge Biomedical
Research Institute (IDIBELL), and Kelly Rabionet,
Center for Genomic Regulation, Barcelona. Over
100 participated in this highly interactive event.
Future Workshops are planned for 2013.
13
Leading Bone Marrow Transplantation
Focusing on:
Haemopoietic Stem Cell Transplantation
The bone marrow transplant programme at UCL-affiliated hospitals is the largest in the U.K., and has pioneered
protocols new being used globally.
The mainstay of treatment for the cancers affecting the blood is chemotherapy and a major side effect of this
chemotherapy is the depression of the normal cells in the bone marrow, resulting in anaemia, low white blood cell
counts which lead to infections and low platelet counts leading to bleeding. Autologous stem cell transplantation is
the procedure whereby the patients own haemopoietic stem cells, normally resident in the bone marrow, are collected, frozen and stored in liquid nitrogen. Very strong chemotherapy can then be given and the patient `rescued’ by
giving back their own stem cells which repopulate the bone marrow grow and replenish the blood. This concept is
not new and attempts to develop this therapeutic approach were made at the Middlesex Hospital (now subsumed
into UCLH) and elsewhere fifty years ago. These attempts were unsuccessful and soon abandoned, and the new
era of stem cell transplantation began in 1980 at UCLH.
Initially stem cells were collected form the bone marrow, but technological advances have allowed most stem cell
harvests to now be collected from the blood, which results in more rapid haematogical recovery. Improvements in
antibiotics and the availability of growth factors have further resulted in the improved safety of these procedures.
Many of these improvements have arisen from clinical trials conducted at UCLH, and the enthusiastic participation
of patients in these trials has been central to the progress made.
Today high dose therapy and autologous stem cell transplantation is standard practice worldwide for patients with
Hodgkin’s disease and non-Hodgkin’s Lymphoma that has not responded adequately to standard therapy. It is
routinely used in multiple myeloma. Equally importantly, the experience gained with the high dose therapy programmes, facilitated the development of higher dose more effective chemotherapy in other situations even when
stem cell rescue is not used.
Haemopoietic stem cell transplants can also be carried out using somebody else’s stem cells. This is called an
allogeneic as opposed to an autologous stem cell transplant. This is a more demanding and risky procedure, but it
does have advantages which must be balanced against these risks. In particular, it is more effective at eliminating
tumour cells because of the immunological response of the grafted cells against the tumour, the so called graft versus tumour effect. The first successful allogeneic transplant in the world was carried out at the Middlesex Hospital
in 1960, but it must be said that the vast majority of attempts at allogeneic transplantation at that time failed. Improved outcomes followed research which provided a better understanding of the haemopoietic system, the immune
system and tissue typing. A major more recent advance has been the development of reduced intensity allogeneic
transplantation which permits the development of a graft versus tumour effect, but with less severe side effects from
the preceding pulse of chemotherapy. UCLH, Great Ormond Street Hospital for Sick Children and the Royal Free
Hospital were involved in the development of these approaches and their regimen is now widely used at other hospitals in the UK and around the world. Allogeneic transplantation is currently used to consolidate the initial remission
in selected patients with acute leukaemia, and it is used at later stages of the disease in leukaemia, lymphoma and
myeloma when autologous transplantation has either failed or is less likely to work.
Today we carry out a mixture of autologous and allogeneic transplants at UCL and its associated hospitals, with
careful selection procedures which involve molecular tests of tumour cells and advanced CT and PET scans, to
determine which is the most appropriate treatment for individual patients. With these strategies, results continue to
improve, and for instance, our results in relapsed and resistant Hodgkin’s disease, which are soon to be published,
are the best reported worldwide. Research continues in our laboratories to feed the ongoing need for progress and
the co-location of the research laboratories in the UCL Cancer Institute opposite the new UCH Macmillan Cancer
Centre cements this link between scientists and clinicians, the University and the Hospital.
This programme is supported by the Medical Research Council, Leukaemia and Lymphoma Research (LLR), Leukaemia and Blood Diseases Research Appeal, CR-UK, the UCLH/UCL Biomedical Research Centre and many other
charities and individuals.
14
Crick news
Key References:
Placebo-controlled phase III trial of lenograstim in bone-marrow transplantation. Gisselbrecht C, Prentice HG, Bacigalupo A, Biron
P, Milpied N, Rubie H, Cunningham D, Legros M, Pico JL, Linch DC, et al. Lancet. (1994) 343(8899), 696-700.
Randomised trial of filgrastim-mobilised peripheral blood progenitor cell transplantation versus autologous bone-marrow transplantation in lymphoma patients. Schmitz N, Linch DC, Dreger P, Goldstone AH, Boogaerts MA, Ferrant A, Demuynck HM, Link H,
Zander A, Barge A. Lancet. (1996) 347(8998), 353-7.
In vivo CAMPATH-1H prevents graft-versus-host disease following Non-Myeloablative stem cell transplantation. Kottaridis PD, Milligan DW, Chopra R, Chakraverty RK, Chakrabarti S, Robinson S, Peggs K, Verfuerth S, Pettengell R, Marsh JC, Schey S, Mahendra P, Morgan GJ, Hale G, Waldmann H, de Elvira MC, Williams CD, Devereux S, Linch DC, Goldstone AH, Mackinnon S. Blood.
(2000) 96(7), 2419-25.
Dose-escalated donor lymphocyte infusions following reduced intensity transplantation: toxicity, chimerism, and disease responses.
Peggs KS, Thomson K, Hart DP, Geary J, Morris EC, Yong K, Goldstone AH, Linch DC, Mackinnon S. Blood. (2004) 103(4), 154856.
Adoptive cellular therapy for early cytomegalovirus infection after allogeneic stem-cell transplantation with virus-specific T-cell lines.
Peggs KS, Verfuerth S, Pizzey A, Khan N, Guiver M, Moss PA, Mackinnon S. Lancet. (2003) 362(9393), 1375-7.
Improved survival after unrelated donor bone marrow transplantation in children with primary immunodeficiency using a reduced-intensity conditioning regimen. Rao K, Amrolia PJ, Jones A, Cale CM, Naik P, King D, Davies GE, Gaspar HB, Veys PA. Blood. (2005)
105(2), 879-85.
Haemopoietic stem-cell transplantation with antibody-based minimal-intensity conditioning: a phase 1/2 study. Straathof KC, Rao K,
Eyrich M, Hale G, Bird P, Berrie E, Brown L, Adams S, Schlegel PG, Goulden N, Gaspar HB, Gennery AR, Landais P, Davies EG,
Brenner MK, Veys PA, Amrolia PJ. Lancet. (2009) 374(9693), 912-20.
Crick News
The Francis Crick Institute will be holding the ‘1st Crick Symposium’ Metabolism in Health and Disease, on Monday 2 July
2012 at the Wellcome Collection Conference Centre, Euston
Road, London. The meeting will discuss the influences of
metabolism upon development, cancer, diabetes, obesity and
ageing. For further details or to book a place please visit the
website:
http://www.crick.ac.uk
The Wonder of Science
Sir Paul Nurse, the Director of the Francis Crick Institute and
President of the Royal Society, spoke of his love for science
and why it matters on the BBC 1’s Richard Dimbleby lecture,
which is given each year in honour of the BBC’s pioneering
journalist. He also spoke of his hope that the Crick would not
just be a place for scientific experiments: “I want to create a
cultural and economic hot house of scientific ideas and applications, to make exciting discoveries improving our health and
driving our economy.”
TRIM27 Target for
Cancer Therapy
The Cancer Research UK supported Group
of Professor Sibylle Mittnacht discovered that
tripartite motif family protein 27 (TRIM27)
levels are significantly increased in common human cancers, including colon and
lung cancers and that mice lacking Trim27
are resistant to chemically induced cancer
development. However, mice lacking Trim27
are not protected from cancers arising as a
consequence of deletion of the Retinoblastoma protein (Rb1). Their data indicate that
TRIM27 is a modifier of cancer incidence
and progression and is a potential target for
cancer drug development.
Key Reference:
Role of the Tripartite Motif Protein 27 in Cancer
Development. Zoumpoulidou G, Broceño C, Li H,
Bird D, Thomas G, Mittnacht S. J Natl Cancer Inst.
(2012), (pre-pub).
To find out more about the Crick Institute you can visit:
The Crick Visitor Centre,
Ossulston Street (opposite Hadstock House),
NW1 1HG.
Opening Times:
Thursdays: 14.00-18.30
Staff will be on hand to answer your questions and you will be
able to see the latest designs and plans for the building.
15
Funding
Selected Recent Funding Awarded
16
Investigator
Funder's Name
Project Title
Award
Martin Pule
BBSRC
ENGINEERING GENETIC REPORTERS FOR IN
VIVO PHOTOACOUSTIC IMAGING OF MAMMALIAN
TISSUES
£465,620
Mary Collins
NIHR
IMPROVING VACCINATION BY TARGETING AND AC£140,888
TIVATING DENDRITIC CELL SUBSETS
Alex Hergovich
BBSRC
SYSTEMATIC MOLECULAR AND CELL BIOLOGICAL
ANALYSIS OF MST KINASE SIGNALLING IN CELL
DEATH CELL CYCLE AND CENTROSOME BIOLOGY
£371,459
Daniel Hochhauser
Merck Serono
INTERACTION OF MEK INHIBITION BY AS703026
AND AS703988 WITH CHEMOTHERAPY
£221,888
Ian Mackie
Arthritis Research UK
PROSPECTIVE RANDOMISED CONTROLLED
PHASE III CLINICAL TRIAL OF RIVAROXABAN
£201,089
Sibylle Mittnacht
Cancer Research UK
ANTI-ONCOGENE TEAM
£301,248
Stephan Beck
EU FP7
A BLUEPRINT OF HAEMATOPOIETIC EPIGENOMES
£508,247
Steen Ooi
ERC
HOW DOES THE X CHROMOSOME REGULATE DNA
£1,123,282
METHYLATION IN PLURIPOTENT STEM CELLS?
Chris Boshoff
Cancer Research UK
KSHV: THE ROLE OF LATENCY TRANSCRIPTS IN
LYMPHATIC ENDOTHELIAL CELL BIOLOGY AND
ONCOGENESIS
£1,260,000
Tariq Enver
Cancer Research UK
CHARACTERISATION OF LEUKAEMIC STEM CELL
BIOLOGY IN CHILDHOOD AML
£880,783
Kazu Tomita
European Research
Council
HIDDEN ROLE OF THE MEIOTIC CHROMOSOMAL
BOUQUET
£1,125,000
Paul Smith
L Hoffman La Roche
A MULTICENTER, PHASE III, OPEN-LABEL, RANDOMIZED STUDY IN PREVIOUSLY UNTREATED PATIENTS WITH ADVANCED INDOLENT NHL EVALUATING THE BENEFIT OF GA101 (RO5072759) PLUS
CHEMOTHERAPY COMPARED WITH RITUXIMAB
£1,689,122
David Linch
Lymphoma Research
Trust
MAINTENANCE AND ANALYSIS OF THE LONGTERM BNLL DATABASE
£602,678
Kwee Yong
GlaxoSmithKline
BCMA PROJECT
£141,523
Hiro Yamano
Cancer Research UK
THE MECHANISMS AND REGULATION OF THE APC/C UBIQUITIN LIGASE SYSTEM
£254,423
Charles Swanton
EU FP7
GENOME BASED BIOMARKERS LEADING TO
VALIDATED MOLECULAR DIAGNOSTIC TESTS FOR
RESPONSE PREDICTION IN BREAST CANCER
£502,761
Kerry Chester
EU FP7
DARTRIX: DARPIN TARGETED MAGNETIC HYPERTHERMIC THERAPY FOR GLIOBASTOMA
£1,852,039
Martin Pule
Leukaemia and
Lymphoma Research
MINIMALLY MANIPULATED ANTI-CD19 CAR AUGMENTED DONOR LEUKOCYTE INFUSION FOR
RELAPSED LYMPHOMA AND LEUKAEMIA
£142,371
Tariq Enver
Cancer Research UK
BECTON DICKINSON ARIA III FLOW SORTER
(Equipment grant)
£154,653
Tim Meyer and
John Hartley
Cancer Research UK
UCL Experimental Cancer Medicine Centre
£248,730
Daniel Hochhauser
Cancer Research UK
AZD8931 IN COMBINATION WITH FOLFIRI - A
PHASE SCHEDULING I / II STUDY
£101,922
Sibylle Mittnacht
AICR
ROLE OF STK4/MST1 SIGNALLING IN RADIATION-MEDIATED G1 CHECKPOINT ACTIVATION
AND RADIATION-RESISTANCE
£200,576
Clare Bennett and
Ron Chakrevarty
Leukaemia and
Lymphoma Research
ANTIGEN PRESENTATION: IDENTIFYING CRITICAL
CHECKPOINTS FOR GVHD AND GVL
£1,272,000