̽��ֱ�� of Cambridge - leukaemia

Scientists develop test to identify people at risk of developing acute myeloid leukaemia and related cancers

jg533 — Thu, 24 Aug 2023 15:14:28 +0000

Researchers at the Wellcome-MRC Cambridge Stem Cell Institute (CSCI), the ̽��ֱ�� of Cambridge’s Department of Haematology, and Instituto de Investigación Sanitaria del Principado de Asturias (ISPA) analysed data from more than 400,000 individuals participating in the United Kingdom Biobank.

Using this data, the scientists created 'MN–predict', a platform for predicting the risk of developing blood cancers such as acute myeloid leukaemia, myelodysplastic syndromes and myeloproliferative neoplasms over a 10- to 15-year period.

̽��ֱ��test, now available in NHS clinics, requires patients to provide a blood sample from which DNA is extracted for limited sequencing, alongside basic blood cell counts. With this information, MN-predict identifies those at high risk of any of these cancers and can be used in specialist clinics for leukaemia prevention.

Professor George Vassiliou, senior author of the study, said: “We all know that prevention is better than cure, but it is not easy to prevent diseases like leukaemia without knowing who is at risk. MN-predict makes it possible to identify at-risk individuals, and we hope it can become an essential part of future leukaemia prevention programmes.”

̽��ֱ��myeloid neoplasms are a group of related cancers encompassing acute myeloid leukaemia, myelodysplastic syndromes and myeloproliferative neoplasms. Treatments for these cancers have improved in the last few years, but most cases remain incurable.

In the last few years, scientists have discovered that these cancers develop over decades through the accumulation of DNA mutations in blood stem cells - the cells responsible for normal blood formation. ̽��ֱ��mutations encourage these stem cells to grow faster than normal and, as more mutations accumulate, they can progress towards leukaemia.

While mutations that promote cell growth are common, leukaemia develops only in a small minority of cases. Identifying these cases early on helps efforts to prevent the cancers from developing.

̽��ֱ��work is published today in the journal Nature Genetics.

Dr Muxin Gu, first author of the paper, said: “We hope that MN-predict will help clinicians to identify people at risk of myeloid cancers, and use novel treatment to prevent the cancers developing.”

Dr Pedro M Quiros, joint senior author of the study, said: “Despite some recent advances in their treatment, unfortunately these cancers remain lethal to many sufferers. We hope that our efforts will help advance prevention in favour of treating the full-blown disease.”

̽��ֱ��research and development of MN-Predict was funded by Cancer Research UK and the Leukaemia and Lymphoma Society. Scientists from the Early Cancer Institute, ̽��ֱ�� of Cambridge, ̽��ֱ�� of Bristol, ̽��ֱ�� of Oviedo (Spain), ̽��ֱ�� of York, AstraZeneca (UK), German Cancer Research Center (DKFZ, Germany), St James's Hospital, Leeds (UK) and ̽��ֱ�� of Pavia (Italy) also participated in the study.

Reference

Gu M, Cheloor-Kovilakam S, Dunn W, Marando L, Barcena C, Mohorianu I, Smith A, Kar S, Fabre M, Gerstung M, Cargo C, Malcovati L, Quiros P, Vassiliou G: 'Multiparameter prediction of myeloid neoplasia risk.' Nature Genetics. 2023. DOI: 10.1038/s41588-023-01472-1

Adapted from a press release by the Wellcome-MRC Cambridge Stem Cell Institute.

̽��ֱ��new ‘MN-predict’ platform will allow doctors and scientists to identify those at risk and to design new treatments to prevent them from developing these potentially lethal cancers.

MN-predict makes it possible to identify at-risk individuals, and we hope it can become an essential part of future leukaemia prevention programmes.

George Vassiliou

Nguyễn Hiệp on Unsplash

Person having a blood test

̽��ֱ��text in this work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Licence type:

Attribution-Noncommerical

Scientists develop new class of cancer drug with potential to treat leukaemia

cjb250 — Mon, 26 Apr 2021 15:00:17 +0000

Our genetic code is written in DNA, but in order to generate proteins – molecules that are vital to the function of living organisms – DNA first needs to be converted into RNA. ̽��ֱ��production of proteins is controlled by enzymes, which make chemical changes to RNA. Occasionally these enzymes become mis-regulated, being produced in over-abundance.

In a study published in 2017, a team led by Professor Tony Kouzarides from the Milner Therapeutics Institute and the Gurdon Institute at the ̽��ֱ�� of Cambridge showed how one such enzyme, METTL3, plays a key role in the development and maintenance of acute myeloid leukaemia. ̽��ֱ��enzyme becomes over-expressed – that is, over-produced – in certain cell types, leading to the disease.

Acute myeloid leukaemia (AML) is a cancer of the blood in which bone marrow produces abnormal white blood cells known as myeloid cells, which normally protect the body against infection and against the spread of tissue damage. AML proceeds rapidly and aggressively, usually requiring immediate treatment, and affects both children and adults. Around 3,100 people are diagnosed with the condition every year in the UK, the majority of whom are over 65 years of age.

Now, Professor Kouzarides and colleagues at STORM Therapeutics, a Cambridge spinout associated with his team, and the Wellcome Sanger Institute, have identified a drug-like molecule, STM2457, that can inhibit the action of METTL3. In tissue cultured from individuals with AML and in mouse models of the disease, the team showed that the drug was able to block the cancerous effect caused by over-expression of the enzyme.

Professor Kouzarides said: “Proteins are essential for our bodies to function and are produced by a process that involves translating our DNA into RNA using enzymes. Sometimes, this process can go awry with potentially devastating consequences for human health. Until now, no one has targeted this essential process as a way of fighting cancer. This is the beginning of a new era for cancer therapeutics.”

To investigate the anti-leukaemic potential of STM2457, the researchers tested the drug on cell lines derived from patients with AML and found that the drug significantly reduced the growth and proliferation of these cells. It also induced apoptosis – ‘cell death’ – killing off the cancerous cells.

̽��ֱ��researchers transplanted cells from patients with AML into immunocompromised mice to model the disease. When they treated the mice with STM2457, they found that it impaired the proliferation and expansion of the transplanted cells and significantly prolonged the lifespan of the mice. It reduced the number of leukaemic cells in the mouse bone marrow and spleen, while showing no toxic side effects, including no effect on body weight.

Dr Konstantinos Tzelepis from the Milner Therapeutics Institute at the ̽��ֱ�� of Cambridge and the Wellcome Sanger Institute added: “This is a brand-new field of research for cancer and the first drug-like molecule of its type to be developed. Its success at killing leukaemia cells and prolonging the lifespans of our mice is very promising and we hope to begin clinical trials to test successor molecules in patients as early as next year.

“We also believe that this approach – of targeting these enzymes – could be used to treat a wide range of cancers, potentially offering us a new weapon in our arsenal against these terrible diseases.”

Michelle Mitchell, Chief Executive of Cancer Research UK, said: "This work is yet another example of how our researchers strive to get new cancer treatments into the clinic and improve outcomes for cancer patients.

"Acute myeloid leukaemia is an aggressive form of cancer which grows rapidly. Treatment is required as soon as possible after diagnosis, which means research like this can't come soon enough.

"We look forward to seeing the outcomes of the phase 1 trial and the benefits it may have for AML sufferers and their families in the future."

̽��ֱ��research was supported by Cancer Research UK, the European Research Council, Wellcome, the Kay Kendall Leukaemia Fund, and Leukaemia UK.

STORM Therapeutics is a ̽��ֱ�� of Cambridge spin-out, supported by Cambridge Enterprise. It specialises in translating research in RNA epigenetics into the discovery of first-in-class drugs in oncology and other diseases.

Reference
Yankova, E, et al. Small molecule inhibition of METTL3 as a therapeutic strategy for acute myeloid leukaemia. Nature; 26 Apr 2021; DOI: 10.1038/s41586-021-03536-w

Scientists have made a promising step towards developing a new drug for treating acute myeloid leukaemia, a rare blood disorder. In a study published today in Nature, Cambridge researchers report a new approach to cancer treatment that targets enzymes which play a key role in translating DNA into proteins and which could lead to a new class of cancer drugs.

Until now, no one has targeted this essential process as a way of fighting cancer. This is the beginning of a new era for cancer therapeutics

Tony Kouzarides

National Cancer Institute

Human cells with acute myelocytic leukemia, shown with an esterase stain at 400x

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. Images, including our videos, are Copyright © ̽��ֱ�� of Cambridge and licensors/contributors as identified. All rights reserved. We make our image and video content available in a number of ways – as here, on our main website under its Terms and conditions, and on a range of channels including social media that permit your use and sharing of our content under their respective Terms.

Yes

Licence type:

Public Domain

New microscopic imaging technology reveals origins of leukaemia

cjb250 — Mon, 19 Oct 2015 13:55:03 +0000

̽��ֱ��researchers studied tiny protein-producing factories, called ribosomes, isolated from cells. They capitalised on improvements made at the LMB to a high-powered imaging technique known as single particle cryo-electron microscopy.

̽��ֱ��microscopes, capable of achieving detail near to the atomic level, enabled the team to link the molecular origins of a rare inherited leukaemia predisposition disorder, ‘Shwachman-Diamond Syndrome’ and a more common form of acute leukaemia to a common pathway involved in the construction of ribosomes.

Cryo-EM map showing the large ribosomal subunit (cyan), eIF6 (yellow) and the SBDS protein (magenta) that is deficient in the inherited leukaemia predisposition disorder Shwachman-Diamond syndrome. Credit: Alan Warren, ̽��ֱ�� of Cambridge

̽��ֱ��research, funded by the blood cancer charity Bloodwise and the Medical Research Council (MRC), is published online in the journal Nature Structural and Molecular Biology.

Ribosomes are the molecular machinery in cells that produce proteins by ‘translating’ the instructions contained in DNA via an intermediary messenger molecule. Errors in this process are known to play a part in the development of some bone marrow disorders and leukaemias. Until now scientists have been unable to study ribosomes at a high enough resolution to understand exactly what goes wrong.

Ribosomes are constructed in a series of discrete steps, like an assembly line. One of the final assembly steps involves the release of a key building block that allows the ribosome to become fully functional. ̽��ֱ��research team showed that a corrupted mechanism underlying this fundamental late step prevents proper assembly of the ribosome.

This provides an explanation for how cellular processes go awry in both Shwachman-Diamond syndrome and one in 10 cases of T-cell acute lymphoblastic leukaemia. This form of leukaemia, which affects around 60 children and young teenagers a year in the UK, is harder to treat than the more common B-cell form.

̽��ֱ��findings from the Cambridge scientists, who worked in collaboration with scientists at the ̽��ֱ�� of Rennes in France, open up the possibility that a single drug designed to target this molecular fault could be developed to treat both diseases.

Professor Alan Warren, from the Cambridge Institute of Medical Research at the ̽��ֱ�� of Cambridge, said: "We are starting to find that many forms of blood cancer can be traced back to defects in the basic housekeeping processes in our cells' maturation. Pioneering improvements to electron microscopes pave the way for the creation of a detailed map of the how these diseases develop, in a way that was never possible before."

Single particle cryo-electron microscopy preserves the ribosomes at sub-zero temperatures to allow the collection and amalgamation of multiple images of maturing ribosomes in different orientations to ultimately provide more detail.

̽��ֱ��technique has been refined in the MRC Laboratory of Molecular Biology by the development of new ‘direct electron detectors’ to better sense the electrons, yielding images of unprecedented quality. Methods to correct for beam-induced sample movements and new classification methods that can separate out several different structures within a single sample have also been developed.

Dr Matt Kaiser, Head of Research at Bloodwise, said: “New insights into the biology of blood cancers and disorders that originate in the bone marrow have only been made possible by the latest advances in technology. While survival rates for childhood leukaemia have improved dramatically over the years, this particular form of leukaemia is harder to treat and still relies on toxic chemotherapy. These findings will offer hope that new, more targeted, treatments can be developed.”

̽��ֱ��research received additional funding from a Federation of European Biochemical Societies (FEBS) Long term Fellowship, the SDS patient charity Ted’s Gang and the Cambridge NIHR Biomedical Research Centre.

Adapted from a press release by Bloodwise

Reference
Weis, F et al. Mechanism of eIF6 release from the nascent 60S ribosomal subunit. Nature Structural and Molecular Biology; 19 Oct 2015

Scientists at the Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge and the Medical Research Council Laboratory of Molecular Biology have taken advantage of revolutionary developments in microscopic imaging to reveal the origins of leukaemia.

Many forms of blood cancer can be traced back to defects in the basic housekeeping processes in our cells' maturation

Alan Warren

PLoS Biology

A Surprising New Path to Tumor Development

̽��ֱ��text in this work is licensed under a Creative Commons Attribution 4.0 International License. For image use please see separate credits above.

Yes

Licence type:

Attribution-ShareAlike

Order matters: sequence of genetic mutations determines how cancer behaves

cjb250 — Wed, 11 Feb 2015 22:00:00 +0000

Most of the genetic mutations that cause cancer result from environmental ‘damage’ (for example, through smoking or as a result of over-exposure to sunlight) or from spontaneous errors as cells divide. In a study published today, researchers at the Department of Haematology, the Cambridge Institute for Medical Research and the Wellcome Trust/Medical Research Council Stem Cell Institute show for the first time that the order in which such mutations occur can have an impact on disease severity and response to therapy.

̽��ֱ��researchers examined genetically distinct single stem cells taken from patients with myeloproliferative neoplasms (MPNs), a group of bone marrow disorders that are characterised by the over-production of mature blood cells together with an increased risk of both blood clots and leukaemia. These disorders are identified at a much earlier stage than most cancers because the increased number of blood cells is readily detectable in blood counts taken during routine clinical check-ups for completely different problems.

Approximately one in ten of MPN patients carry mutations in both the JAK2 gene and the TET2 gene. By studying these individuals, the research team was able to determine which mutation came first and to study the effect of mutation order on the behaviour of single blood stem cells.

Using samples collected primarily from patients attending Addenbrooke’s Hospital, part of the Cambridge ̽��ֱ�� Hospitals, researchers showed that patients who acquire mutations in JAK2 prior to those in TET2 display aberrant blood counts over a decade earlier, are more likely to develop a more severe red blood cell disease subtype, are more likely to suffer a blood clot, and their cells respond differently to drugs that inhibit JAK2.

Dr David Kent, one of the study’s lead authors, says: “This surprising finding could help us offer more accurate prognoses to MPN patients based on their mutation order and tailor potential therapies towards them. For example, our results predict that targeted JAK2 therapy would be more effective in patients with one mutation order but not the other.”

Professor Tony Green, who led the study, adds: “This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy. These results show how study of the MPNs provides unparalleled access to the earliest stages of tumour development (inaccessible in other cancers, which usually cannot be detected until many mutations have accumulated). This should give us powerful insights into the origins of cancer.”

Work in the Green Lab is supported in part by Leukaemia and Lymphoma Research and Cancer Research UK.

Dr Matt Kaiser, Head of Research at Leukaemia & Lymphoma Research, said: “We are becoming more and more aware that a cancer’s genetic signature can vary from patient to patient, and we are becoming better at personalising treatment to match this. ̽��ֱ��discovery that the order in which genetic errors occur can have such a big impact on cancer progression adds an important extra layer of complexity that will help tailor treatment for patients with MPNs. ̽��ֱ��technology to do this sort of study has been available only recently and it shows once again how pioneering research into blood cancers can reveal fundamental insights into cancer in general.”

Dr Áine McCarthy, Science Information Officer at Cancer Research UK, says: “ ̽��ֱ��methods used in this pioneering research could help improve our understanding of how cancer cells develop mutations and when they do so. This interesting study suggests that the order in which genetic faults appear can affect how patients respond to different drugs – this insight could help doctors personalise treatment to make it more effective for each patient.”

Reference
Ortmann, CA and Kent, DG et al. ̽��ֱ��Impact of Mutation Order on Myeloproliferative Neoplasms. NEJM; 11 Feb 2015

Additional funding came from the Kay Kendall Leukaemia Fund; the NIHR Cambridge Biomedical Research Centre; the Cambridge Experimental Cancer Medicine Centre; the Leukemia & Lymphoma Society of America; the Canadian Institutes of Health Research; and the Lady Tata Memorial Trust.

̽��ֱ��order in which genetic mutations are acquired determines how an individual cancer behaves, according to research from the ̽��ֱ�� of Cambridge, published today in the New England Journal of Medicine.

This is the first time that mutation order has been shown to affect any cancer, and it is likely that this phenomenon occurs in many types of malignancy

Tony Green

geralt

Red blood cells (illustration)

̽��ֱ��text in this work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page. For image rights, please see the credits associated with each individual image.

Yes

Licence type:

Attribution-Noncommercial-ShareAlike

Computer model of blood development could speed up search for new leukaemia drugs

cjb250 — Mon, 09 Feb 2015 16:00:00 +0000

̽��ֱ��human body produces over 2.5 million new blood cells during every second of our adult lives, but how this process is controlled remains poorly understood. Around 30,000 new patients each year are diagnosed with cancers of the blood each year in the UK alone. These cancers, which include leukaemia, lymphoma and myeloma, occur when the production of new blood cells gets out of balance, for example if the body produces an overabundance of white blood cells.

Biomedical scientists from the Wellcome Trust-MRC Cambridge Stem Cell Institute and the Cambridge Institute for Medical Research collaborated for the past 2 years with computational biologists at Microsoft Research and Cambridge ̽��ֱ��’s Department of Biochemistry. This interdisciplinary team of researchers have developed a computer model to help gain a better understanding of the control mechanisms that keep blood production normal. ̽��ֱ��details are published today in the journal Nature Biotechnology.

“With this new computer model, we can carry out simulated experiments in seconds that would take many weeks to perform in the laboratory, dramatically speeding up research into blood development and the genetic mutations that cause leukaemia,” says Professor Bertie Gottgens whose research team is based at the ̽��ֱ��’s Cambridge Institute for Medical Research.

Dr Jasmin Fisher from Microsoft Research and the Department of Biochemistry at the ̽��ֱ�� of Cambridge says: “This is yet another endorsement of how computer programs empower us to gain better understanding of remarkably complicated processes. What is ground-breaking about the current work is that we show how we can automate the process of building such programs based on raw experimental data. It provides us with a blueprint to develop computer models relevant to other human diseases including common cancers such as breast and colon cancer.”

To construct the computer model, PhD student Vicki Moignard from the Stem Cell Institute measured the activity of 48 genes in over 3,900 blood progenitor cells that give rise to all other types of blood cell: red and white blood cells, and platelets. These genes include TAL1 and RUNX1, both of which are essential for the development of blood stem cells, and hence to human life.

Computational biology PhD student Steven Woodhouse then used the resulting dataset to construct the computer model of blood cell development, using computational approaches originally developed at Microsoft Research for synthesis of computer code. Importantly, subsequent laboratory experiments validated the accuracy of this new computer model.

One way the computer model can be used is to simulate the activity of key genes implicated in blood cancers. For example, around one in five of all children who develop leukaemia has a faulty version of the gene RUNX1, as does a similar proportion of adults with acute myeloid leukaemia, one of the most deadly forms of leukaemia in adults. ̽��ֱ��computer model shows how RUNX1 interacts with other genes to control blood cell development: the gene produces a protein also known as Runx1, which in healthy patients activates a particular network of key genes; in patients with leukaemia, an altered form of the protein is thought to suppress this same network. If the researchers change the ‘rules’ in the network model, they can simulate the formation of abnormal leukaemia cells. By tweaking the leukaemia model until the behaviour of the network reverts back to normal, the researchers believe they can identify promising pathways to target with drugs.

Professor Gottgens adds: “Because the computer simulations are very fast, we can quickly screen through lots of possibilities to pick the most promising ones as pathways for drug development. ̽��ֱ��cost of developing a new drug is enormous, and much of this cost comes from new candidate drugs failing late in the drug development process. Our model could significantly reduce the risk of failure, with the potential to make drug discovery faster and cheaper.”

̽��ֱ��research was supported by the Medical Research Council, the Biotechnology and Biological Sciences Research Council, Leukaemia and Lymphoma Research, the Leukemia and Lymphoma Society, Microsoft Research and the Wellcome Trust.

Dr Matt Kaiser, Head of Research at UK blood cancer charity Leukaemia & Lymphoma Research, which has funded Professor Gottgens’ team for over a decade, said: “For some leukaemias, the majority of patients still ultimately die from their disease. Even for blood cancers for which the long-term survival chances are fairly good, such as childhood leukaemia, the treatment can be really gruelling. By harnessing the power of cutting-edge computer technology, this research will dramatically speed up the search for more effective and kinder treatments that target these cancers at their roots.”

Reference
Moignard, V et al. Decoding the regulatory network of early blood development from single-cell gene expression measurements. Nature Biotech; 9 Feb 2015.

̽��ֱ��first comprehensive computer model to simulate the development of blood cells could help in the development of new treatments for leukaemia and lymphoma, say researchers at the ̽��ֱ�� of Cambridge and Microsoft Research.

With this new computer model, we can carry out simulated experiments in seconds that would take many weeks to perform in the laboratory

Bertie Gottgens

E. M. Unit, Royal Free Hospital

SEM image of normal red blood cells, computer-coloured red

Yes

Scientists demonstrate potential new treatment for most common form of infant leukaemia

gm349 — Mon, 03 Oct 2011 08:35:03 +0000

Cambridge scientists have shown that a potential new drug could treat mixed-lineage leukaemia (MLL), the most common form of leukaemia in babies, according to a study published in Nature yesterday (02 October).

MLL leukaemia is thought to account for up to 80 per cent of children below two years of age diagnosed with acute leukaemia, and up to one in 10 cases in adults. Most patients don’t respond well to standard leukaemia treatments and often the cancer comes back.

̽��ֱ��disease is caused when a gene called MLL gets fused to another gene. This disrupts the normal function of MLL by creating a new ‘fusion protein’ that behaves inappropriately, switching on genes that drive the development of leukaemia.

̽��ֱ��research team - based at the Wellcome Trust/Cancer Research UK Gurdon Institute and the Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge and with funding from the Cancer Research UK – collaborated with scientists from GlaxoSmithKline (GSK) and Cellzome AG to identify that the MLL-fusion proteins are targeted to leukaemia-causing genes by proteins from the BET family, which recognise certain chemical ‘tags’ on chromatin, the scaffold on which DNA is organised.

Together the researchers showed that a new chemical agent developed by GSK – I-BET151 - mimics these chemical tags, preventing BET and MLL from attaching to chromatin and activating the leukaemia genes. Treatment of leukaemias in mice and human cancer cells in the lab showed that the chemical could halt the disease, paving the way for its use in patient trials.

Study co-leader Professor Tony Kouzarides, deputy director of the Wellcome Trust/Cancer Research UK Gurdon Institute at the ̽��ֱ�� of Cambridge, said: “Our work shows that this type of leukaemia is reliant on MLL being able to bind to chromatin via BET proteins. This “epigenetic” approach to therapy - which targets chromatin rather than DNA - is an exciting new avenue for drug discovery which we hope will be useful for other types of cancer in addition to MLL-leukaemias.”

Dr Brian Huntly, who co-led the study and is based at the Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge, said: “MLL leukaemia is very hard to treat and often the only option for patients who have become resistant to standard treatments is a bone marrow transplant. We hope these findings may in future mean that fewer children need this procedure.”

Dr Lesley Walker, Cancer Research UK’s director of cancer information, said: “Cancer Research UK has played an important role in progress being made in childhood leukaemia, with eight in ten children now surviving more than five years compared to fewer than one in ten in the late 1960s. But there is still more work to do and we urgently need better ways to treat children with more aggressive forms of leukaemia, such as MLL. Although this research is only in the lab at the moment, we hope it will move quickly towards clinical trials in patients.”

New drug could treat mixed-lineage leukaemia (MLL).

MLL leukaemia is very hard to treat and often the only option for patients who have become resistant to standard treatments is a bone marrow transplant. We hope these findings may in future mean that fewer children need this procedure.

Dr Brian Huntly, who co-led the study and is based at the Cambridge Institute for Medical Research at the ̽��ֱ�� of Cambridge

Flickr: Amy Loves Yah

Beakers

This work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page.

Yes

Understanding how cancer cells grow

bjb42 — Mon, 04 Jan 2010 14:30:05 +0000

Most tissues in the human body are maintained by stem cells – master builders and repairers that replenish different types of cells when needed. ̽��ֱ��unique properties of stem cells are of great interest to scientists investigating the possibility of regenerating and repairing human tissues. But stem cells have also come under close scrutiny in relation to cancer, since the ability to self-renew is a characteristic of tumours. Research into cancer stem cells is offering new insight into how cancer cells grow and how some tumours relapse even following powerful therapy.

Cambridge has a very active stem cell community, recognised as a centre of excellence by the Wellcome Trust (WT) and the Medical Research Council (MRC). A major research theme within this community is the Cancer Stem Cell Programme at the MRC Centre for Stem Cell Biology and Regenerative Medicine. Professor Fiona Watt, who directs the Programme, explained why cancer stem cells are so interesting: ‘Pathologists have known for centuries that within a single tumour there can be cells that differ in maturity. It is now becoming clear that this heterogeneity reflects, at least in part, the existence of cancer stem cells and their offspring, and that these cells play a crucial role in the life history of cancer. Eradicating these master builders would strike at the heart of the tumour.’

Cancer stem cells

̽��ֱ��Cancer Stem Cell Programme brings together clinicians and scientists with expertise in haematological, epithelial and brain cancers.

One of the best-studied adult stem cell systems is the process by which the many different cell types found in blood are constantly replenished. Professor Tony Green and Dr Brian Huntly in the Department of Haematology are using this process as a paradigm for understanding leukaemias: ‘We are especially interested in the molecular rewiring that underlies the change from a normal cell to a cancerous stem cell,’ explained Professor Green. A recent success has been the discovery of a new molecular mechanism for leukaemia.

To identify cancer stem cells and their complex interactions, researchers frequently develop biological models of cancer. Dr Stephen Goldie in Professor Watt’s lab, in collaboration with clinicians at Cambridge ̽��ֱ�� Hospitals NHS Foundation Trust, is investigating cancer stem cells in human head and neck tumours by creating models that recapitulate the original human tumour. ‘Interactions between the tumour and its environment are being tracked by state-of-the-art imaging technology to establish which cells are responsible for making the tumours and what can be done to make the tumour shrink and stop spreading,’ explained Dr Goldie.

Scientists from the Centre for Brain Repair in the Department of Clinical Neurosciences and the WT Centre for Stem Cell Research are investigating stem cells in brain cancer. ‘Brain cancer accounts for a disproportionate number of cancer deaths and new treatments are urgently required,’ explained Dr Colin Watts, Consultant Neurosurgeon, from the Centre for Brain Repair. ‘These tumours contain stem-like cells that are resistant to current treatments. Work in the Centre aims to understand the mechanisms underlying this resistance and to develop ways of killing these cells.’

Driving new treatments

̽��ֱ��current thinking is that cancer stem cells constitute a minority of the cells within a tumour and, although they are capable of dividing continually, they may do so relatively slowly. Most therapies are targeted towards rapidly dividing cells, which might kill the bulk of the tumour but not the cancer stem cells. Understanding more about cancer stem cells is therefore crucial, as Professor Watt explained: ‘Future treatments that are specific for cancer stem cells will not only be more effective in treating the disease, but will also incur less collateral damage to the patient’s normal tissues.’

For more information, please contact Professor Fiona Watt (fiona.watt@cancer.org.uk), the Herchel Smith Professor of Medical Genetics, at the Wellcome Trust-MRC Stem Cell Institute and the Cancer Research UK Cambridge Research Institute/Li Ka Shing Centre.

Cambridge scientists are asking what role stem cells play in how cancer develops, spreads and relapses.

Kim Jensen

Stem cells

This work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page.

Yes

Watching cancer cells eat, breathe and die

bjb42 — Mon, 04 Jan 2010 14:27:46 +0000

Increasing the speed and sensitivity of detecting how tumour cells are responding to treatment is something of a Holy Grail in the field of oncology. Treatment response is still largely assessed by looking for a reduction in tumour size using magnetic resonance imaging (MRI) or X-ray computed tomography. But many tumours may take weeks or even months to show evidence of regression and, in some cases, may not regress at all despite a positive response to treatment. How can an earlier indication of response be achieved so that clinicians can select the best treatment for an individual patient?

New techniques are being pioneered in Cambridge to ‘see’ tumour cells as never before. Research in Professor Kevin Brindle’s laboratory is developing a variety of clinically applicable, non-invasive, imaging techniques that measure tumour cells ‘eating, breathing and dying’.

Spin doctor

One approach under investigation by the Brindle lab is based on MRI. Although this technique has been around since the 1970s, the new imaging method has a crucial difference – instead of detecting the distribution and properties of water protons in tissue, which conventional MRI does, the new approach detects with much greater sensitivity than ever before the small molecules in tissues that are fundamental to their biochemistry. These are the carbon-based metabolites involved in producing energy and in making the constituents of the cell; a change in how these metabolites are being used can signal that an effective therapy is starting to kill the cells.

̽��ֱ��problem with carbon-based molecules is that they are present in tiny amounts compared with the protons in tissue water, making them hard to detect and almost impossible to image at high resolution. To overcome this, the Brindle group has been collaborating with GE Healthcare to develop a technique that increases MRI sensitivity by more than 10,000 times.

To achieve such a dramatic increase in sensitivity, the scientists have turned to nuclear spin hyperpolarisation. Before intravenous injection, a molecule labelled with an MR isotope of carbon is hyperpolarised so that a large proportion of the carbon nuclear spins line up with the magnetic field, as opposed to only a few in a million in a conventional MR experiment. ̽��ֱ��resulting gain in sensitivity means that the researchers can watch how the hyperpolarised carbon is metabolised by tumours, using this as a read-out for living and dying cells. Data published recently have shown how well this technique works for monitoring treatment response, and the first clinical trials are planned to start in 2010.

Personalising medicine

Different tumours are likely to require different imaging methods. With recent funding from the Leukaemia and Lymphoma Society, a new study has just begun in which several of the imaging methods under development in the Brindle group are being validated in models of lymphoma, so that the best reagents and protocols can be selected for future clinical trials.

Improved imaging methods are not only useful in the clinic, but will also be invaluable for early stage clinical trials of new drugs, where the need to establish whether new treatments are working is particularly acute. Professor Brindle is working with Professor Duncan Jodrell and Dr David Tuveson at the Cancer Research UK Cambridge Research Institute to develop imaging methods that allow treatment responses in individual patients to be measured immediately. Because patients with similar tumour types can show markedly different responses to the same therapy, imaging will be an important component of the armoury of ‘personalised medicine’, enabling the most effective treatment to be tailored to specific patients.

For more information, please contact Professor Kevin Brindle (kmb1001@cam.ac.uk) at the Department of Biochemistry and the Cancer Research UK Cambridge Research Institute/Li Ka Shing Centre. This research was published in Proceedings of the National Academy of Sciences (2009) 106, 19801–19806 and was funded principally by Cancer Research UK, with material support from GE Healthcare.

Cancer cells can now be viewed as never before, thanks to cutting-edge imaging tools being developed in Cambridge.

Kevin Brindle

Lymphoma

This work is licensed under a Creative Commons Licence. If you use this content on your site please link back to this page.

Yes