Promising pre-clinical results for targeted treatment of colorectal cancer
Despite extensive efforts to improve the clinical management of patients with colorectal cancer, approved treatments for advanced colorectal cancer (CRC) offer limited survival benefit. Therefore, the identification of novel treatment strategies is essential. Recent research led by Dr Vessela Vassileva, writing in the Journal of Nuclear Medicine, has revealed that we may be a step closer to finding a new targeted therapy that offers a real improvement in the treatment of this type of cancer.
Dr Vassileva explains: “We evaluated the efficacy of combination radioimmunotherapy with cetuximab in pre-clinical models of CRC. Our results demonstrate enhanced therapeutic benefit, which could potentially translate into successful clinical outcomes.”
“Cetuximab is already approved for use, however it is not used for patients who have KRAS gene mutations, as it is generally accepted that such mutations render cetuximab ineffective. However, our results indicated that the presence of KRAS mutations is not sufficient to negatively affect the efficacy of the combined radioimmunotherapy/cetuximab treatment and that further mutations in this signalling pathway are required to render treatment ineffective. All of the pre-clinical models that we tested had a KRAS mutation, and they all responded, except for the one that had further mutations, such as PI3K.”
Evidence from the research suggests that the combination therapy can deliver highly targeted radiotherapy to cancer cells - leaving healthy cells unharmed - and use far lower radiation doses while still delivering therapeutic benefits when used in combination.
Dr Vassileva adds: “The combined treatment we have been investigating has the potential to target not only a primary tumour but could also be effective against metastatic tumours, which may not have been identified. These tumours would be selectively ‘found’ by the therapy and treatment would become active against the cancer cells. It is this selective targeting that offers a way of reducing toxicity to provide safer and more effective treatment.”
Journal of Nuclear Medicine - paper
Effect of Tumour Biology on Therapeutic Response - Research Group
New Wellcome Trust Senior Research Fellow
UCL Cancer Institute’s Dr Suzana Hadjur, has been awarded a Wellcome Trust Senior Research Fellowship. The prestigious award - provided by the Trust to fund outstanding researchers - will support Dr Hadjur’s work in examining fundamental aspects of genome organization and function. Her group will study the molecular transitions which accompany cellular development and how structural configurations of chromatin collaborate with transcription factors to drive differentiation.
Dr Hadjur says: “Our research group is fascinated by the structure and organization of chromosomes in nuclear space and how such complex spatial packaging of the genome influences fundamental cellular processes such as cell division, genome integrity and gene regulation. Current research focuses on the contribution of the architectural proteins, CTCF and cohesin to three-dimensional genome organization. In addition, we are inspired by recent studies describing cohesin proteins as key players in cancer development. Thus, we have an interest in testing if cohesin’s roles in genome organization contribute to the transition of normal cells towards cancer.”
“This research provides fundamental biological insights into normal cellular behaviour. Discoveries from our work will provide a platform upon which to further understand cancer progression, cellular reprogramming and developmental biology. I am very proud to be a Wellcome Trust Senior Fellow. It is a great achievement for my lab and I hope this encourages other women scientists.”
Hadjur Lab - Genome Organisation and Function
Wellcome Trust Fellowship
UCL News - profile
Thursday 14 May, 2015
Smoking induces early signs of cancer in cheek swabs
DNA damage caused by smoking can be detected in cheek swabs, finds research published today in JAMA Oncology. The study provides evidence that smoking induces a general cancer program that is also present in cancers which aren’t usually associated with it – including breast and gynaecological cancers.
The research team, led by Professor Martin Widschwendter (UCL Institute for Women's Health and Dr Andrew Teschendorff (UCL Cancer Institute) looked at epigenetic alterations – changes to the DNA that switch genes on and off. Epigenetic changes are associated with cancer development and can be caused by exposure to environmental factors such as cigarette smoke.
The researchers aimed to explore whether normal cells from the inside of the cheek would demonstrate epigenetic changes which are associated with lung and other epithelial cancers. These types of cancers originate in the epithelial cells – which cover the outside of the body as skin or the inside of the body as lining for organs and body cavities – and make up 85% of all cancer cases in the UK. The buccal cells taken from the cheek swabs are easy to collect and are directly exposed to cigarette smoke in those who smoke.
To do this, in collaboration with Prof Diana Kuh (UCL Epidemiology & Public Health) and her team, they analysed buccal samples from 790 women all born in 1946 and 152 matched blood samples from the Medical Research Council National Survey of Health and Development. The dataset included information about smoking history and smoking status at the time the samples were collected.
This analysis showed that buccal cells in women who have smoked had numerous changes to their epigenomes – known as DNA-methylation (DNAme). Buccal cells showed a 40-fold increase in abnormal methylation sites compared to matched blood samples, making them a more reliable indicator of DNA changes.
The team then went on to analyse this smoke-triggered epigenetic program in over 5000 tissue samples, including normal tissue, pre-cancerous tissue and cancer tissue from 15 different epithelial cancer types. In doing so, they tested whether they were able to discriminate normal tissue from cancerous tissue. They found that this program – which they originally derived in normal buccal cells of smokers – is able to discriminate between normal and cancerous tissue with almost 100% sensitivity and 100% specificity irrespective of the organ from which the cancer arose.
Researchers also found that the absence or presence of this program was able to predict the fate of pre-invasive cancer lesions. The presence of the faulty program in the cells makes it very likely that a pre-invasive cancer will progress to a full-blown invasive cancer. However, the absence of the faulty program makes it likely that the pre-cancer can potentially regress and disappear.
An individuals’ DNA works like the hardware within a cell, with the epigenome being the software. Smoking misprograms the epigenome and the genetic code becomes difficult or impossible to read. Misprogramming of a cells’ software, in conjunction with genetic mutations, eventually lead to an inability of these cells to develop into specific differentiated cells. These cells are then trapped in an undifferentiated status and can grow indefinitely and spread into other organs.
Lead author Dr Andrew Teschendorff, UCL Cancer Institute said: “Our work shows that smoking has a major impact on the epigenome of normal cells that are directly exposed to the carcinogen. Of particular significance is that these epigenetic changes are also seen in both smoking-related and non-smoking related cancers, pointing towards a universal cancer program. This research gets us closer to understanding the very first steps in carcinogenesis and in future may provide us with much-needed tests for risk prediction and early detection.”
Research paper - JAMA Oncology
Friday 17 April, 2015
Scientists decipher key steps in cancer development to improve treatment
Scientists have discovered the timing of key genetic mistakes that fuel tumour growth, according to research published in the journal Science Translational Medicine today.
The findings begin to reveal patterns that are common in many cancer types and provide crucial evidence that, as cancer develops, the growth of the disease may rely on gene mutations present in only a small number of cells within the tumour. "I’m optimistic that we’ll one day be able to use evolutionary theory to outsmart many cancers" - Professor Charles Swanton, study author at the Francis Crick Institute and the UCL Cancer Institute.
This uncovers vital clues explaining why tumours become resistant to treatment and suggests new strategies for tackling the problem.
The researchers trawled through publicly available data for over 2,500 tumours from The Cancer Genome Atlas to study the variety of mutations, and the processes that trigger them, across nine common cancer types. Understanding which genetic faults are driving the growth and spread of disease at different time points could help develop new targeted drugs or drug combinations aimed at genetic changes present in all rather than just a minority of tumour cells. This could reveal ways of forcing tumours down an ‘evolutionary dead end’ that makes it much less likely resistant cancer cells will be left behind to carry on growing after treatment.
Professor Charles Swanton said: “Data from large-scale sequencing studies offer a snapshot of all the cells in a tumour at a particular moment in time. We have used a phenomenal public resource provided by the Cancer Genome Atlas in the USA to drill down further to work out how cancers change over time and to attempt to identify genetic events that in turn drive a tumour’s growth and ability to spread.
“This has enabled us to sift out some of the really important genetic faults occurring in all tumour cells from those that may play less of a role, or appear in only a few cells. It’s only the tip of the iceberg but I’m optimistic that we’ll one day be able to use evolutionary theory to outsmart many cancers, using carefully orchestrated combinations of drugs, and therapies that harness the body’s immune system, at key time points.”
Cancer Research UK
Science Translational Medicine
Friday 2 April, 2015
Body’s cancer defences hijacked to make pancreatic and lung cancers more aggressive
Scientists have discovered that a vital self-destruct switch in cells is hijacked - making some pancreatic and non small cell lung cancers more aggressive, according to research published in Cancer Cell today.
The team, from the Cancer Research UK Centre at the UCL Cancer Institute, found that mutations in the KRAS gene interferes with protective self-destruct switches, known as TRAIL receptors, which usually help to kill potentially cancerous cells.
The research, shows that in cancers with faulty versions of the KRAS gene these TRAIL receptors actually help the cancer cells to grow and spread to new areas in the body. These KRAS faults occur in 95 per cent of pancreatic cancers (Pancreatic ductal adenocarcinoma) and 30 per cent of non small cell lung cancers.
Professor Henning Walczak, lead researcher of the study and scientific director of the Cancer Research UK-UCL Centre, said: “Our research has unveiled a new strategy used by some pancreatic and non small cell lung cancers to overcome our body’s natural defences against cancer. By understanding the faults in these cancers we think we can develop more tailored treatments, which could one day provide urgently-needed options for patients with these types of pancreatic and non small cell lung cancers.”
Each year in Great Britain 32,500 people are diagnosed with non small cell lung cancer and around 8,600 people are diagnosed with pancreatic cancer. Survival for these cancers has not shown much improvement for 40 years.
Nell Barrie, senior science information manager at Cancer Research UK, said: “Sadly survival from pancreatic and lung cancers remains far too low, partly because these cancers are very difficult to treat once they have spread.
“We urgently need better treatments, so it’s vital to delve deeper into the molecular workings of these cancers to find ways to combat them. This research may one day help us find a way to block cancer spread, which would be a vital step to save more lives.”
Cancer Research UK
Research Paper in Cancer Cell
Thursday 26 March, 2015
New role uncovered for tumour suppressor retinoblastoma gene
Scientists have revealed a brand new function for one of the first cancer genes ever discovered – the retinoblastoma gene – in a finding that could open up exciting new approaches to treatment.
The retinoblastoma gene is so called because mutations to it cause a rare children’s eye cancer of the same name, and is known to play a central role in stopping healthy cells from dividing uncontrollably.
Now the new study – jointly led by scientists at The Institute of Cancer Research, London, and UCL Cancer Institute– has found that the gene also has another important function, in helping to ‘glue’ severed strands of DNA back together.
The research suggests that existing drugs that exploit the weaknesses of some cancers in repairing their DNA could be effective against tumours with mutations to the retinoblastoma gene. The study, published today (Thursday) in the journal Cell Reports, was funded by a range of organisations including Cancer Research UK, Worldwide Cancer Research, the Wellcome Trust and The Institute of Cancer Research (ICR) itself.
Professor Sibylle Mittnacht, Leader of the Cancer Cell Signalling team and Professor of Cancer Biology at the UCL Cancer Institute, said: “We are very excited about this new discovery. Our work demonstrates that loss of the retinoblastoma gene promotes major defects in cancer DNA which drives the evolution to a more aggressive and therapy resistant form in major cancers such as breast and lung cancers. At the same time, this discovery points to exciting prospects for new and more effective ways in which these cancers can be treated..”
Dr Paul Huang, Team Leader in Cancer Biology at The Institute of Cancer Research, London, said:
“The retinoblastoma gene was one of the first cancer genes to be discovered and is one of the best known of all, so it’s very exciting to have been able to identify a completely new function for it. The retinoblastoma gene is famous for helping control cell division, but we found that it has another important job in gluing broken strands of DNA back together. Our research could have real implications for cancer patients, because drugs that exploit weaknesses in DNA repair already exist, and there is now a rationale for testing them against cancers with retinoblastoma gene mutations.”
Tuesday 10 March, 2015
New therapy developed to treat lung cancer to be tested in patients
A pioneering new technique has been developed that uses gene therapy and stem cell therapy in combination to treat lung cancer. Researchers led by Professor Sam Janes, Professor of Respiratory Medicine at UCL and and Consultant in Respiratory Medicine at UCLH, will carry out the first UK clinical trial in NHS patients later this year. The treatment uses stem cells as a delivery vehicle for a potent anti-cancer gene, which induces a self-destruct pathway in cancer, but not healthy cells.
The therapy works by modifying donor stem cells so that they express an anti-cancer gene called TRAIL*. Being encased within a cell protects the genetic material from being degraded by the body so that when it reaches the tumour it is able to trigger a signalling pathway that kills the cancer cells.
Each patient in the trial will receive almost a billion cells over three infusions, three weeks apart (injected one day after they receive chemotherapy). Over the next three years 100 billion cells will be created at the Royal Free Hospital’s £2.1 million, state-of-the-art cell manufacturing lab, which is run by Dr Mark Lowdell, director of cellular therapy and biobanking at the Royal Free London NHS Foundation Trust.
Principle Investigator Sam Janes, said: “Lung cancer is very difficult to treat because the vast majority of patients are not diagnosed until the cancer has spread to other parts of the body. We aim to improve prospects for lung cancer by using a highly targeted therapy using stem cells. Once there, they switch on a ‘kill’ pathway in the cancer cells, leaving healthy surrounding cells untouched.
He added: “If clinical trials are successful, our treatment could be transformative for the treatment of lung cancer, and possibly other types of tumour in future.”
* Tumour Necrosis Factor related Apoptosis-Inducing Ligand (TRAIL)
Medical Research Council
Thursday 11 December 2014, 12:00noon
Special Seminar: Dr Trever Bivona, University of California
Department of Medicine, Division of Hematology and Oncology, University of California, San Francisco
Courtyard Café, Paul O’Gorman Building (Map)
Dr Trever Bivona
Improving mechanism-based therapy of lung cancer
Dr Bivona is a laboratory-based physician-scientist and an academic medical oncologist with a Ph.D. in cell and molecular biology. Clinical experiences inspire his laboratory’s investigations and provide opportunities to translate scientific discoveries aimed at improving the personalized treatment of cancer patients. The goal of his research program is to define the molecular pathogenesis of human cancers through both basic and translational studies with a particular focus on lung cancer, the leading cause of cancer mortality in the United States.
Seminar is followed by a sandwich buffet lunch
6 October 2014; 6pm Monday
Special Seminar: Professor Hilary Calvert Retirement Lecture
Special Seminar - 6pm Monday - 6th October
Wilkins Gustave Tuck Lecture Theatre (Map)
Professor Hilary Calvert
In search of the Achilles Heels of Cancers: reflections on a misspent career
Professor Hilary Calvert has had an outstanding career spanning over 40 years. He has made substantial advances in research and anti-cancer drug development and his clinical commitment has led to innovative and lasting contributions that continue to benefit patients today.
Followed by a reception in the Courtyard Café, Paul O'Gorman Building
All are welcome
25 September 2014
UCL Cancer Institute achieved the Athena Swan Silver Award !
Under the leadership of Professor Kerry Chester the Institute has been successful in achieving Silver Athena SWAN status.
The awards, announced today, recognise commitment to advancing women's careers in science, technology, engineering, maths and medicine in higher education and research.
Seven institutions, including two research institutes, achieved their first ever Athena SWAN award in the first of two awards rounds this year. Overall, 83 higher education institutions, research institutes and individual schools and departments will receive awards.
The University College London - UCL Cancer Institute achieved a prestigious Silver department award.
Click here to see the Athena Swan 2014 results.
16 January 2014
Tolerance of Whole-Genome Doubling Propagates Chromosomal Instability and Accelerates Cancer Genome Evolution
Published in: Cancer Discovery (Online).
Dewhurst SM, McGranahan N, Burrell RA, Rowan AJ, Grönroos E, Endesfelder D, Joshi T, Mouradov D, Gibbs P, Ward RL, Hawkins NJ, Szallasi Z, Sieber OM, Swanton C.
The contribution of whole-genome doubling to chromosomal instability (CIN) and tumor evolution is unclear. We use long-term culture of isogenic tetraploid cells from a stable diploid colon cancer progenitor to investigate how a genome-doubling event affects genome stability over time. Rare cells that survive genome doubling demonstrate increased tolerance to chromosome aberrations. Tetraploid cells do not exhibit increased frequencies of structural or numerical CIN per chromosome. However, the tolerant phenotype in tetraploid cells, coupled with a doubling of chromosome aberrations per cell, allows chromosome abnormalities to evolve specifically in tetraploids, recapitulating chromosomal changes in genomically complex colorectal tumors. Finally, a genome-doubling event is independently predictive of poor relapse-free survival in early-stage disease in two independent cohorts in multivariate analyses [discovery data: hazard ratio (HR), 4.70, 95% confidence interval (CI), 1.04-21.37; validation data: HR, 1.59, 95% CI, 1.05-2.42]. These data highlight an important role for the tolerance of genome doubling in driving cancer genome evolution.
Original research article can be found at:
See also: Editorial in New Scientist
6 October 2013
Women with recurrent ovarian cancer survive longer after treatment with cediranib
Presented at: the 2013 European Cancer Congress (ECC2013) ( Online).
Professor Jonathan Ledermann
Abstract no: LBA10. “Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: Results of the ICON6 trial”. Presidential session III, 12.30 hrs CEST, Monday 30 September, Hall 7.1.
Women with ovarian cancer that has recurred after chemotherapy have survived for longer after treatment with a biological therapy called cediranib, according to new results to be presented today (Monday) at the 2013 European Cancer Congress (ECC2013).
Cediranib, which is taken in pill form, is an inhibitor of a cell signalling process involved in formation of tumour blood vessels, essential for tumour growth, and it is the first oral inhibitor of its kind to show an improvement in the time before patients' disease progresses and in overall survival. The drug is a tyrosine kinase inhibitor, a type of biological therapy that blocks vascular endothelial growth factor (VEGF) receptors, which control the development of blood vessels required for growing tumours.
Professor Jonathan Ledermann, Professor of Medical Oncology at UCL Cancer Institute, University College London, presented first results from ICON6, an international randomised, double-blind, academic clinical phase III trial of cediranib.
"In women whose ovarian cancer had been treated with platinum-based chemotherapy together with cediranib given during and after the chemotherapy, we found that the time before the tumour started to grow again was extended by an average of 3.2 months. This sounds like a modest increase but represents about a 30% improvement, with overall survival also increased by a similar amount, to an average of 2.7 months over a two-year period of follow-up," he said.
Studies with chemotherapy alone have shown that the time before patients experience disease progression following treatment for a relapse that is sensitive to platinum-based chemotherapy is an average of eight to nine months. These latest results show that cediranib in addition to chemotherapy increased the time before the disease progressed from 9.4 to 12.6 months over a period of two years, and it extended overall survival from 17.6 to 20.3 months.
"These are ground-breaking data," said Prof Ledermann. "Cediranib is the first oral VEGF tyrosine kinase inhibitor that has been shown to delay tumour progression and improve overall survival in recurrent ovarian cancer. It is simple to give for a prolonged period and in most patients it is well-tolerated." Adverse side-effects included high blood pressure, diarrhoea and fatigue.
A total of 456 patients whose ovarian cancer had recurred were enrolled in the trial in 63 centres from the UK, Canada, Australasia and Spain. They were randomised to receive platinum-based chemotherapy together with a placebo (the reference arm of the trial), or 20 mg a day of cediranib during chemotherapy followed by placebo for 18 months (concurrent arm of the trial), or 20 mg a day of cediranib during chemotherapy followed by cediranib as a maintenance treatment (maintenance arm).
"ICON6 has a three-arm design in which the effect of cediranib given with chemotherapy and continued as maintenance can be compared with standard chemotherapy. This is the first trial to have demonstrated a benefit of concurrent cediranib with chemotherapy, as well as demonstrating an additional benefit with maintenance cediranib," he said.
An increased survival time of nearly three months is significant in this group of patients. Prof Ledermann explained: "In previous ovarian cancer trials any improvement seen with each new treatment has been incremental. Survival has improved through sequential use of drugs. Most of the recent positive trials have shown an improvement in progression-free survival. Trials showing an improvement in overall survival are uncommon. Cediranib produces an incremental improvement in progression-free survival and an incremental improvement in overall survival. Although the average improvement in overall survival is 2.7 months, some patients will see a much more substantial benefit."
ECCO president, Professor Cornelis van de Velde, commented: "These are important results for women with recurrent ovarian cancer. Once the disease has recurred there are few treatment options available that make a significant difference to its progression and to overall survival. The ICON6 trial shows that cediranib does make a difference and it is to be hoped that it can be made available to women as soon as is practicable."
SOURCE European CanCer Organisation (ECCO)
24 July 2013
Foot and Mouth Disease Virus used to target Cancer
Published in: Plos One 2013 ( Online).
Kogelberg* H, Miranda* E, Burnet J, Ellison D, Tolner B, Foster J, Picón C, Thomas GJ, Meyer T, Marshall JF, Mather SJ and Chester K
*These authors contributed equally to this work !
PLoS One. 2013 Sep 4;8(9):e73260. doi: 10.1371/journal.pone.0073260.
Scientists at the UCL Cancer Institute working to develop treatments for cervical cancer have harnessed a part of the foot-and-mouth disease virus to create a genetically engineered antibody fragment designed to target cancer. The work, sponsored by the ‘Debbie Fund’ (www.debbiefund.org) and published today in the international open access journal PLOS ONE, showed that the new antibody reduced cancer cell migration, was able to target radioactivity to solid tumours and was internalised into cancer cells. This therefore has implications for the spread of cancer and could provide a new route for delivering targeted treatment.
Researchers at the UCL Cancer Institute worked in collaboration with teams at The Barts Cancer Institute and Southampton Cancer Research UK to produce the new antibody which will be manufactured in yeast cells. It binds to the avß6 integrin, a protein that promotes tumour activity.
Professor Chris Boshoff, Director of the UCL Cancer Institute, commented: “The results of this research show promise for a range of potential applications in imaging, function blocking or targeted delivery of therapeutic agents within cancer treatment”.
“This new antibody brings us an important step closer to a new treatment for patients with cervical cancers” said Kerry Chester, Professor of Molecular Medicine, and one of the lead investigators of the Debbie Fund project.
The Debbie Fund was set up in memory of Debbie Phillips, who died of cervical cancer in 2010. During the progression of Debbie’s disease, her family and friends discovered that worldwide there was no dedicated research into a drug treatment specifically for cervical cancer and the fund was established to raise finance for this essential research. The Debbie Fund is also supporting further studies at the UCL Cancer Institute, using advanced DNA sequencing technologies and functional screens to decipher and exploit the genetic code of cervical cancer for the development of improved treatments.
Clinical experts Dr Mary McCormack and Professor Tim Meyer commented: “There is an urgent need to develop new and better therapies for patients with cervical cancer, so the innovative approaches which Debbie Fund is supporting are extremely important in potentially improving outcomes for patients in the future.”
The research was also supported by Cancer Research UK, the Experimental Cancer Medicine Centre, UCL Cancer Institute Research Trust and NIHR.
Original research article can be found at:
24 July 2013
Meta-analysis of IDH-mutant cancers identifies EBF1 as an interaction partner for TET2
Published in: Nat Commun. 2013 ( Online).
Guilhamon P, Eskandarpour M, Halai D, Wilson GA, Feber A, Teschendorff AE, Gomez V, Hergovich A, Tirabosco R, Fernanda Amary M, Baumhoer D, Jundt G, Ross MT, Flanagan AM, and Beck S.
Nat Commun. 2013 Jul 17;4:2166. doi: 10.1038/ncomms3166.
Cancer is a disease of the genome caused predominantly by mutations and epimutations (changes to the chemical marking of the DNA rather than the sequence itself). By comparing such epimutations in cancers with and without specific mutations, Guilhamon and colleagues discovered a novel targeting mechanism explaining why certain genes are more affected in the mutant cancers.
Isocitrate dehydrogenase (IDH) genes 1 and 2 are frequently mutated in acute myeloid leukaemia (AML), low-grade glioma, cholangiocarcinoma (CC) and chondrosarcoma (CS). For AML, low-grade glioma and CC, mutant IDH status is associated with a DNA hypermethylation phenotype, implicating altered epigenome dynamics in the aetiology of these cancers. Here we show that the IDH variants in CS are also associated with a hypermethylation phenotype and display increased production of the oncometabolite 2-hydroxyglutarate, supporting the role of mutant IDH-produced 2-hydroxyglutarate as an inhibitor of TET-mediated DNA demethylation. Meta-analysis of the acute myeloid leukaemia, low-grade glioma, cholangiocarcinoma and CS methylation data identifies cancer-specific effectors within the retinoic acid receptor activation pathway among the hypermethylated targets. By analysing sequence motifs surrounding hypermethylated sites across the four cancer types, and using chromatin immunoprecipitation and western blotting, we identify the transcription factor EBF1 (early B-cell factor 1) as an interaction partner for TET2, suggesting a sequence-specific mechanism for regulating DNA methylation.
7 July 2013
In vivo imaging of glucose uptake and metabolism in tumors
Published in: Nat Med. 2013 ( Online).
Walker-Samuel S, Ramasawmy R, Torrealdea F, Rega M, Rajkumar V, Johnson SP, Richardson S, Gonçalves M, Parkes HG, Arstad E, Thomas DL, Pedley RB, Lythgoe MF, and Golay X.
Nat Med. 2013 Jul 7. doi: 10.1038/nm.3252.
Sugar makes cancer light-up in MRI scanners
A new technique for detecting cancer by imaging the consumption of sugar with magnetic resonance imaging (MRI) has been unveiled by UCL scientists. The breakthrough could provide a safer and simpler alternative to standard radioactive techniques and enable radiologists to image tumours in greater detail.
The new technique, called ‘glucose chemical exchange saturation transfer’ (glucoCEST), is based on the fact that tumours consume much more glucose (a type of sugar) than normal, healthy tissues in order to sustain their growth.
The researchers found that sensitising an MRI scanner to glucose uptake, caused tumours to appear bright on MRI images of mice.
Lead researcher Dr Simon Walker-Samuel, from the UCL Centre for Advanced Biomedical Imaging (CABI) said: “GlucoCEST uses radio waves to magnetically label glucose in the body. This can then be detected in tumours using conventional MRI techniques. The method uses an injection of normal sugar and could offer a cheap, safe alternative to existing methods for detecting tumours, which require the injection of radioactive material.”
Professor Mark Lythgoe, Director of CABI and a senior author on the study, said: “In principal, we can detect cancer using the equivalent amount of sugar as found in half a standard sized chocolate bar.
“MRI uses standard imaging technology available in many large hospitals,” he continued. “Our research reveals a useful and cost-effective method for imaging cancers. In the future, patients could potentially be scanned in local hospitals, rather than being sent for referrals to specialist medical centres.”
According to UCL’s Professor Xavier Golay, another senior author on the study: “Our cross disciplinary research could allow vulnerable patient groups such as pregnant women and young children to be scanned more regularly, without the risks associated with a dose of radiation.”
The study has been published in the journal Nature Medicine and trials are now underway to detect glucose in human cancers.
Dr Walker-Samuel added: “We have developed a new state-of-the-art imaging technique to visualise and map the location of tumours that will hopefully enable us to assess the efficacy of novel cancer therapies.”
This work was supported by public and charitable funding from the Department of Health’s NIHR Biomedical Research Centres funding scheme, Cancer Research UK, Engineering and Physical Sciences Research Council (EPSRC) and the British Heart Foundation (BHF).
16 June 2013
The genetics of chondrosarcoma – a novel link with a gene related to the production of cartilage – COL2A1
Published in: Nat Genet. 2013 ( Online).
Tarpey PS, Behjati S, Cooke SL, Van Loo P, Wedge DC, Pillay N, Marshall J, O'Meara S, Davies H, Nik-Zainal S, Beare D, Butler A, Gamble J, Hardy C, Hinton J, Jia MM, Jayakumar A, Jones D, Latimer C, Maddison M, Martin S, McLaren S, Menzies A, Mudie L, Raine K, Teague JW, Tubio JM, Halai D, Tirabosco R, Amary F, Campbell PJ, Stratton MR, Flanagan AM, Futreal PA.
Nat Genet. 2013 Jun 16. doi: 10.1038/ng.2668 [Epub ahead of print]
Researchers from UCL Cancer Institute, The Wellcome Trust Sanger Institute and the Royal National Orthopaedic Hospital screened the functioning regions of the genome in 49 patients with chondrosarcoma. They found that mutations in the gene COL2A1, a gene central to the production of cartilage, played a role in cancer development in almost 40 per cent of the patients.
COL2A1 is the gene for a type of collagen. Collagens are fibrous proteins that are responsible for the tensile strength of bone, cartilage and other tissues. This collagen is particularly important for the development of cartilage and thus the gene is very active in cartilage cells. This is the first time that a collagen gene has been shown to be involved in the development of a cancer. The team speculates that the high activity of COL2A1 in cartilage cells could contribute to the formation of mutations that underlie the development of chondrosarcoma.
The team also uncovered the Indian Hedgehog pathway that contributes to the development of this bone cancer in one in five patients with the disease. Drugs that inhibit this pathway already exist, and therefore the team's finding offers potential new treatment options for many patients with this cancer type.
Chondrosarcoma is a cancer of cartilage and is the second most common type of primary bone cancer. The main treatment option is surgery as chemotherapy or traditional radiotherapy provides no significant benefit for patients with this disease. This study offers new approaches to diagnosing this tumour and possible new treatments.
The team looked at the activity of COL2A1 in other bone cancers but did not find mutations. The high frequency of mutation in COL2A1 in chondrosarcoma patients could therefore become a diagnostic marker to differentiate it from other bone cancers.
Monday 24 June 2013
UCL Cancer Institute – SPECIAL SEMINAR
5pm, Monday 24th June 2013
J Z Young Lecture Theatre, Anatomy Building – entrance off Gower Street (location)
The Hippo-YAP pathway in organ size control and tumorigenesis
Professor Kun-Lianag Guan, University of California, San Diego.
Prof. Kun-Liang Guan has a long standing interest in understanding mammalian signal transduction cascades. His research mainly focuses on signal transduction mechanisms regulating cell growth and organ size. While researching the roles of the TSC-mTOR pathway in cell size control and nutrient signalling by studying biosynthesis and autophagy he has also over the past 5 years made ground breaking discoveries in the Hippo tumour suppressor signalling field. His laboratory has described how Hippo signalling controls the proto-oncoproteins YAP/TAZ by spatial (nucleo-cytoplasmic shuttling) and temporal (protein stability) regulatory mechanisms, in addition to establishing that Hippo signalling is regulated by cell attachment, cell-cell contacts as well as G-protein coupled receptor (GPCR) signalling. He has published influential papers in highly ranked peer-reviewed journals, thereby establishing key roles of Hippo signalling in stem cell and cancer cell biology. Here, Prof. Guan, who is adjunct professor at the universities of Michigan, Fudan and Zhejiang in addition to his post at the University of California, will focus on presenting recent progress in Hippo signalling, a novel intracellular signal transduction cascade in control of cell death, proliferation and differentiation.
Host: Alexander Hergovich (email@example.com)
More information on Prof. Kun-Liang Guan and his research can be found at:
Selected publications over the past years:
Yu, F.X., et al. Genes Dev. 2013 Jun 1;27(11):1223-32.
Russell, R.C., et al. Nat Cell Biol. 2013 May 19. doi: 10.1038/ncb2757.
Zhao, D., et al. Cancer Cell. 2013 Apr 15;23(4):464-76.
Kim, J., et al. Cell. 2013 Jan 17;152(1-2):290-303.
Tumaneng, K., et al. Nat Cell Biol. 2012 Dec;14(12):1322-9.
Mo, J.S., et al. Genes Dev. 2012 Oct 1;26(19):2138-43.
Yu, F.X., et al. Cell. 2012 Aug 17;150(4):780-91.
Xiao, M., et al. Genes Dev. 2012 Jun 15;26(12):1326-38.
Lian, I., et al. Genes Dev. 2010 Jun 1;24(11):1106-18.
Zhao, S., et al. Science. 2010 Feb 19;327(5968):1000-4.
Zhao, B., et al. Genes Dev. 2010 Jan 1;24(1):72-85.
Mori, H., et al. Cell Metab. 2009 Apr;9(4):362-74.
Kim, E., et al. Nat Cell Biol. 2008 Aug;10(8):935-45.
Zhao, B., et al. Genes Dev. 2008 Jul 15;22(14):1962-71.
Zhao, B., et al. Genes Dev. 2007 Nov 1;21(21):2747-61.
Inoki, K., et al. Cell. 2006 Sep 8;126(5):955-68.
Full publication list:
All are welcome. A reception will be held after the seminar in the Courtyard Café, Paul O’Gorman Building.
Tuesday 28 May 2013
Tyrosine Kinase BMX Phosphorylates Phosphotyrosine-Primed Motif Mediating the Activation of Multiple Receptor Tyrosine Kinases
Published in: Science Signaling, May 28, 2013 (Online).
S. Chen*, X. Jiang*, C. A. Gewinner*, J. M. Asara, N. I. Simon, C. Cai, L. C. Cantley, S. P. Balk
*Authors contributed equally to this work
Sci. Signal. 6, ra40 (2013), pp.1-11
The Tec family tyrosine kinase BMX (bone marrow tyrosine kinase gene on chromosome X) is broadly expressed and activated downstream of phosphatidylinositol-3 kinase (PI3K) and SRC, but its substrates are unknown. Positional scanning peptide library screening with which the optimal phosphorylation motif of kinases can be determined, revealed a marked preference of BMX for a priming phosphotyrosine (pY) in the -1 position (the amino acid before the BMX phosphorylation site). This indicates that BMX substrates may include multiple tyrosine kinases with kinase domain pYpY sites required for full activity.
We found that BMX phosphorylated Y577 in the focal adhesion kinase (FAK) subsequent to Y576 phosphorylation by SRC. Further, we demonstrated that BMX loss using RNAi technology or Bmx-/- murine embryonic fibroblasts (MEFs) lead to markedly impaired FAK activity proving the direct involvement of BMX phosphorylation in FAK activity. In addition, we identified that insulin receptor (IR) phosphorylation at the kinase domain (Y1189/1190 and Y1185 sites) and downstream serine/threonin k