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  • Our milestones: the discovery of the NRAS signalling gene - Cancer Research UK - Science blog
    the Cancer Research Campaign They decided to search for oncogenes using a technique developed by US researchers where DNA from cancer cells is inserted into healthy cells to see if it will make them cancerous This search for oncogenes required a range of scientific skills but their backgrounds made them an ideal team Marshall was fascinated by the behaviour of cells the biological building blocks that make up our bodies Meanwhile Hall was a molecular biologist interested in the genetic nuts and bolts inside cells that made them tick They were keen to prove themselves and dreamed the dream of all explorers to discover something new something fundamental in keeping with the scientific spirit of the time they wanted to find their very own oncogene It sounds like a simple idea but it was a trying time for the pair They had no luck for almost a year Even when they knew they d sucessfully modified their laboratory grown cells with DNA from cancer cells they didn t find any signs of oncogenes The pressure was mounting and The ICR s head Prof Robin Weiss was getting impatient Marshall and Hall were beginning to wonder if they were wasting their time As a last resort they decided to analyse another 20 DNA samples and if nothing panned out they would drop the idea and focus on something else Then they finally struck gold DNA from two different tumour cells showed evidence of an oncogene And they were quickly able to show that it was probably the same oncogene in the two different tumours And a close look at the DNA recipe of their new gene revealed that it looked similar to two oncogenes called HRAS and KRAS which had recently been discovered by researchers in the US After some discussion with their US counterparts Marshall and Hall decided to name this new gene NRAS They published their landmark discovery in the June 1983 issue of the journal Nature Researchers now know the 3D shape of RAS proteins It turns out that about 12 per cent of all human cancers contain a faulty HRAS KRAS or NRAS gene making these genes among the most mutated genes in cancer And some cancer types are more likely to have a RAS mutation such as pancreatic cancer while in others such as breast cancer such faults are quite rare RAS oncogenes can also be cancer specific for example in pancreatic cancers that contain a RAS mutation it is always KRAS that s faulty But in melanomas and leukaemias it s usually NRAS We still don t know why different cancer types have different RAS mutations But their discovery in human tumours momentous in itself is only the start of the story Once the genes identities had been uncovered researchers were able to turn their attention to the next fundamental question how do they cause cancer Sending signals Thanks to the painstaking work of hundreds of cancer researchers Hall and Marshall included we now know the answer In healthy cells the proteins made by RAS genes are switched on by incoming signals from the cell s exterior and then proceed to switch on other proteins like a molecular game of pass the parcel This is known as an intracellular signalling pathway and the end result is the activation of genes required for a cell to grow and divide In most of our cells RAS proteins are usually inactive and only turned on when the cell gets a signal to multiply But in cancer the faulty RAS oncogene produces a defective protein that is always switched on In turn this means the signalling pathway is always active leading to the unchecked frenzy of cell growth and division that defines cancer Having discovered NRAS Chris Marshall s lab went on to make the important discovery that RAS proteins control a key signalling pathway called the MAP kinase pathway We now know that when it becomes active RAS activates members of a second family of proteins called the RAF family which then activate a protein called MEK which in turn activates one called MAPK ultimately setting the wheels in motion for cell division A simple diagram of the MAP Kinase pathway And it turns out that if any of the other parts of this pathway become oncogenic and misbehave a cell can become cancerous This seemingly simple mechanism a defect that allows the cell to keep dividing endlessly lies at the heart of most cancers Indeed this very independence from external growth signals is one of the so called hallmarks of cancer Passing it on The field of cell signalling has since exploded with thousands of research papers published over the past three decades dissecting a whole host of pathways in intricate detail Scientists who worked with Marshall and Hall went on to set up their own successful labs forming their own highly active collaborative and sometimes competitive network of cell signalling researchers Through their discoveries we are learning that how our cells communicate is not so much about straightforward lines of proteins talking to each other as about intricate signalling webs layers upon layers of feedback loops and cross talk knitting together pathways once thought to be separate Untangling this and understanding how it goes wrong in cancer has been vital for developing new drugs to target overactive or broken signalling proteins And this approach has already been successful in several new cancer treatments Although we don t yet have cancer treatments that can directly switch off any of the RAS family members for a variety of reasons they re particularly tricky targets for designing drugs against many researchers around the world are working on it and there are glimmers of hope on the horizon But even if we can t target RAS itself thankfully other parts of the MAP kinase pathway are more amenable For example drugs that block activation of MEK are now being tested in clinical trials while drugs that block BRAF are now

    Original URL path: http://scienceblog.cancerresearchuk.org/2015/04/29/our-milestones-the-discovery-of-the-nras-signalling-gene/ (2016-02-11)
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  • Discovering the p53 cancer protein - Cancer Research UK - Science blog
    heavier than expected Something was indeed sticking to it There also seemed to be another smaller protein present although they needed to work out if it was actually a new protein or just a smaller fragment of a known viral protein Further experiments showed that this was indeed a new protein with a molecular weight of 53 000 Daltons 53 kiloDaltons Hence the name p53 protein of 53kiloDaltons Since there was simply not enough genetic room in the SV40 virus s DNA to make an additional protein the only conclusion that Lane and Crawford could draw was that the protein was originating from the mouse cells The paper predicts that It is possible that the mystery protein may normally act as a regulator of certain cellular functions related to growth control It is of prime importance to determine the level of this protein in normal cells and to see if it is induced by other carcinogenic agents On the other side of the Atlantic while Lane and Crawford were carrying out their experiments researchers Arnold Levine at Princeton University and Lloyd Old at Sloane Kettering Memorial Hospital were also coming to the same conclusion via a different route What impact has the research had Twenty years later researchers are only just getting to grips with the complex role that p53 plays within the cell how it is involved in cancer and whether they can use this knowledge to design new treatments for the disease A recent review by Professor Carol Prives and Cancer Research UK s Professor Karen Vousden highlights how far we have come and how far we still have to go in understanding this complicated molecule The human gene that encodes p53 TP53 was uncovered in 1984 We now know that one of p53 s key jobs is to act as a transcription factor responsible for turning genes on in response to DNA damage This has earned p53 the nickname the guardian of the genome It helps to protect us from cancer by causing cells to stop growing or even die in response to damage You can see it at work if you ve ever been sunburnt the resulting peeling skin is the result of p53 switching on a cell suicide pathway inside damaged cells helping to protect us from skin cancer at least most of the time Molecular Swiss Army knife But p53 may perform other jobs too Since its discovery it s been proposed to be involved in cell death cell sleep senescence ageing metabolism immunity embryo implantation cell eating autophagy DNA repair growth of new blood vessels angiogenesis and cellular stress It probably makes the tea and does the washing up as well On top of this and highlighting its ubiquitous role in normal cell function researchers now know that p53 is faulty or switched off in many human cancers But despite this attempts to reactivate it in cancer cells haven t been altogether successful so far Scientists including Professor Lane are still studying p53

    Original URL path: http://scienceblog.cancerresearchuk.org/2009/10/04/high-impact-science-p53/ (2016-02-11)
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  • From yeast to sea urchins - the story of a Nobel prize - Cancer Research UK - Science blog
    a child he d been fascinated by the wildlife around his childhood home As a teenager this interest extended to experimenting on fruit flies and collecting beetles But as an adult he turned his attention to studying yeast cells that have been treated in certain ways to encourage faults in random genes Paul figured that if the genes controlling cell division were faulty then some yeast cells might divide more slowly growing unusually large But others might divide faster forming smaller than average cells Sure enough he soon noticed some unusually big cells that seemed to be unable to start the division process These turned out to have a fault in a gene called cdc2 which is essential for getting the DNA copying process started and then later on splitting it into two daughter cells Another piece of the puzzle slotted into place in 1982 when Paul showed that cdc2 gene in his yeast was the same as Lee Hartwell s CDC28 Perhaps he thought this gene might also be the same in other types of cells The big breakthrough came once Paul moved to the Imperial Cancer Research Fund ICRF labs in 1984 today part of the Cancer Research UK London Research Institute to escape the long Scottish winter nights It wasn t an entirely smooth move as he faced scepticism from other scientists in the Institute who couldn t see how yeast was relevant to cancer But their views were about to change Paul along with a member of his research team Melanie Lee embarked on a bold experiment to find the human version of cdc2 They took a whole bunch of human genes and added them one at a time to yeast lacking the cdc2 gene that were unable to divide It was a long shot but to their surprise one of them worked thanks to the extra human gene the yeast could happily divide as if nothing was wrong The implications of their results published in the journal Nature in 1987 were profound Despite being separated by 1 5 billion years of evolution Melanie and Paul s work suggested that the fundamental engine driving the cell cycle is the same in all species Subsequent work by our researchers and others around the world has proved this to be true across many of the engine s molecular parts More findings came to light Paul and another ICRF researcher Viesturs Simanis showed that the cdc2 gene makes a type of protein molecule known as a kinase These are the cell s messengers passing signals around by sticking chemical flags on other proteins This discovery gave a strong hint that the processes governing the cell cycle might be controlled by these messenger molecules In fact cdc2 later became known as CDK 1 or cyclin dependent kinase 1 the first in a family of half a dozen similar genes that are all involved in cell division And it s here in our story that we meet the other missing part of the puzzle cyclin and our other Nobel laureate Tim Hunt Going on a cyclin trip Tim Hunt While Paul Nurse was looking at yeast cells to work out how they divided Cambridge University biochemist Tim Hunt was tackling a more prickly customer the sea urchin Fascinated by science from a young age he even dissected his brother s pet rabbit when it died Tim had become intrigued by the unusual ability of unfertilised sea urchin eggs to spontaneously start dividing and developing when dunked in soapy water Scientists refer to this phenomenon as parthenogenesis roughly translated from the Greek words for virgin birth To understand what was going on required a steady supply of sea urchin eggs something that was sorely lacking in land locked Cambridge so Tim headed across the pond to Woods Hole Marine Biological Laboratory for the 1982 summer urchin season Perched on a harbour on the Massachusetts coast it s a perfect place for studying sea life Late one night while his lab mates were out dancing at a local pub he noticed something strange He d been looking at the molecules produced by parthenogenetic sea urchin eggs as they started dividing But while most of the molecules stayed the same one behaved very differently just as the cells divided for the first time it vanished Nobody had ever seen this kind of thing before so Tim started to look more closely He discovered that the levels of the mysterious protein peaked just as the cells got ready to divide then it completely disappeared as they split Fond of cycling Hunt named this protein cyclin as a play on the fact that its levels cycled around Returning to Cambridge after the summer Tim continued to explore this vanishing act Together with graduate student Jon Pines now a long standing Cancer Research UK scientist in his own right and professor at Cambridge he identified the gene encoding cyclin in sea urchins and clams In an echo of Paul and Melanie s yeast experiments Tim and Jon showed that the sea urchin cyclin gene could kick start cell division in frog eggs proving that it worked across species Since then cyclins have been found in all cells with an impressive assortment of different cyclins in humans In 1990 Tim moved to the ICRF s Clare Hall laboratories in Hertfordshire part of the Cancer Research UK London Research Institute today and has made many more significant contributions to our understanding of how cells divide Putting the engine together Between them Lee Hartwell Paul Nurse and Tim Hunt identified the crucial components of the engine that drives the cell cycle And they along with many other researchers across the globe have spent the last 35 years figuring out how it works It turns out that cyclin is a bit like the engine itself spinning through cycles of creation and destruction The CDKs are the gears pairing up with their appropriate cyclin at the right time When a CDK gets

    Original URL path: http://scienceblog.cancerresearchuk.org/2014/10/06/from-yeast-to-sea-urchins-the-story-of-a-nobel-prize/ (2016-02-11)
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  • Finding faults in the BRAF gene - Cancer Research UK - Science blog
    and what did they find The scientists started by taking DNA from 15 samples of cancers 6 breast cancers one small cell lung cancer 6 non small cell lung cancer one malignant melanoma and one mesothelioma a type of lung cancer Crucially the researchers also had access to healthy cells from the original patients as well They compared the DNA sequence of the BRAF gene in the samples and found three important occasions where the sequence in the cancer cells differed from that of the healthy cells by just one DNA letter base pair The BRAF gene is faulty in more than half of all melanoma skin cancer Thinking that these differences could be important in cancer the researchers widened their study to look at DNA taken from 530 samples of cancer cells that had been grown in the lab called cell lines They found faults in BRAF in 43 of the cancer cell lines including 20 out of 34 melanoma samples and 7 out of 40 bowel cancer samples as well as a smaller proportion of other cancer types All the BRAF faults they had identified were clustered around two particular points within the gene They homed in on these regions using a further 378 tumour samples from patients with a range of different cancer types The results were striking faults in BRAF were found in over two thirds of the melanoma samples and a smaller proportion of bowel and ovarian cancers The final part of the puzzle was to figure out how the faults in BRAF might lead to cancer Usually faults in genes mean that the protein they produce is faulty and doesn t work properly But in this case the scientists discovered that the BRAF faults they identified actually send the gene into overdrive This means that it sends too many signals telling the cell to divide a direct link to cancer In fact one specific fault can increase the activity of BRAF by up to five hundred times fuelling the runaway growth of cancer cells What impact has this work had At the end of their paper the researchers themselves noted The high frequency of BRAF mutations in melanoma and the relative lack of effective therapies for advanced stages of this disease suggest that inhibition of BRAF activity may be an important new strategy for the treatment of metastatic melanoma In other words designing drugs that specifically block BRAF could lead to urgently needed treatments for malignant melanoma once it has spread Researchers suggest that around 5 000 people die every year from different cancers with BRAF faults and around 7 out of ten melanomas are caused by BRAF faults so the stakes are high To this end Cancer Research UK has continued to fund research into BRAF In 2004 a team at the Institute of Cancer Research led by Professor Richard Marais analysed the structure of overactive BRAF from cancer cells and compared it with BRAF taken from healthy cells press release They found

    Original URL path: http://scienceblog.cancerresearchuk.org/2009/08/24/high-impact-science-%e2%80%93-finding-faults-in-braf/ (2016-02-11)
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  • EGFR – Wanna be starting something? - Cancer Research UK - Science blog
    to understand how it worked Get into the groove Proteins are made of long chains of smaller building blocks called amino acids The exact order of amino acids in the chain causes it to twist tangle and loop producing a distinctive three dimensional structure This gives each protein its personality allowing it to do its proper job in a cell So to reveal the secrets contained within EGFR s nooks and crannies Dr Downward had to work out its exact amino acid sequence something that had hadn t been done before He started by isolating large quantities of EGFR from human cancer cells using innovative techniques pioneered by colleagues in his lab Next he took the chemical equivalent of a sledgehammer and smashed EGFR up into tiny pieces These were then fed one by one into a machine developed by researchers in the lab called a gas phase sequencer which chewed them up and spat out their amino acid sequence Finally Downward had what he needed and his detective work could begin What a feeling He started by asking whether his amino acid sequences were present in other molecules Proteins that share similar arrangements of amino acids along their length often do similar jobs inside cells so was this the case with EGFR Again he was in the right place for the job as his benchmate Geoff Scrace was maintaining one of the few existing databases of all known protein sequences Downward fed in his EGFR sequence data and waited His Eureka moment finally came three months later when the computer came up with a match EGFR was almost identical to v erb B a protein produced by a virus that causes cancer in chickens To Downward s amazement this cancer causing virus protein was simply a neatly trimmed version of our own EGFR This was a huge shock It suggested that altering a cell s own proteins could propel cancer growth The findings proved that the seeds of cancer are within us as Nobel prize winning scientist J Michael Bishop famously proposed Downward s work was published in the prestigious journal Nature where like a nerdy version of Michael Jackson s chart topping album Thriller it caused a sensation within the research community Labs investigating the role of EGFR in cancer suddenly mushroomed all over the world propelling EGFR biology to the forefront of cancer research It wasn t long before changes in EGFR were linked to a myriad of cancer types and a sister protein HER2 was discovered to play a critical role in certain types of breast cancer These results together with others from scientists around the world prompted a question that would change the face of cancer therapeutics If molecules like EGFR and HER2 propelled cancer growth would blocking them kill tumours With this the targeted therapies revolution was born Never gonna give you up Fast forward to today Rick Astley may have made an inexplicable comeback for the amusement of bored office workers but Downward

    Original URL path: http://scienceblog.cancerresearchuk.org/2011/08/05/high-impact-science-egfr/ (2016-02-11)
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  • From snapshot to family tree – writing the evolutionary rule book of cancer - Cancer Research UK - Science blog
    about half the families have six fingers on each hand while the rest have five So this genetic alteration must have happened after the hair colour back when there were only two families in the clan one family got the six finger mutation so all their descendants will also carry it the other didn t Finally you see that each family within the clan has different coloured eyes red yellow green purple and more as well as all kinds of other quirky unique traits This diversity reveals that the gene changes responsible for this large range of differences must be recent as they re specific to each family rather than shared among the whole clan Straightaway this is enough information to build a simple evolutionary tree showing how the families must have split over time as well as the evolutionary relationships of the underlying genetic faults the hair gene changed first then the gene for finger number then eye colour and everything else creating a branching and diverse family tree And it s the same for the tumour snapshots within the TGCA database Trunk or branch Using these same principles Nicky was able to figure out whether certain mutations had happened early on when the cancer first started growing known as trunk mutations or later events the branches of the family tree by looking at the proportions of different genetic alterations in the data for each tumour sample Although there were variations in the particular genes that were mutated in individual tumour samples across the different cancer types he noticed a recurring pattern common to many of them Watch an animation explaining how targeted cancer treatments work Certain genetic changes known to be key drivers of cancer growth tended to happen early on in cancer development and were found in all the tumour cells But sometimes important mutations including those hit by the new generation of targeted drugs such as vemurafenib Zelboraf affected a smaller proportion of the cancer cells suggesting they were turning up later on This finding helps to explain why targeted therapies often seem to work well for a while in some cases dramatically shrinking patients tumours only for the disease to return with a vengeance months or even years down the line In these situations Nicky and Charles suspect that although the drugs may be targeting many of the families of the cancer s entire clan some groups of cancer cells are unaffected by the treatment This explains why cancers can return after treatment as these remaining drug resistant cells continue to grow and evolve Importantly it appears that many of the mutations that happen early on during cancer development are in genes that have proved to be extremely difficult to hit with targeted therapies such as a gene called Ras Although our scientists and others around the world are working hard on these undruggable targets they re not there yet However this discovery does suggest that drugs designed to target these mutations could form the

    Original URL path: http://scienceblog.cancerresearchuk.org/2015/04/15/from-snapshot-to-family-tree-writing-the-evolutionary-rule-book-of-cancer/ (2016-02-11)
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  • More progress in detecting oesophageal cancer early - Cancer Research UK - Science blog
    people at risk of developing cancer Enter the Cytosponge We ve talked a lot about this nifty sponge on a string device in the past and you can watch how it works by watching the video below Watch how the Cytosponge works in this video New data So what s new The BEST2 trial has now recruited over 1000 patients from Centres across the country half of whom had Barrett s oesophagus the other half didn t To test the performance of the Cytosponge every participant on the trial first had to swallow the small sponge containing capsule Next each patient went on to have the slightly more cumbersome standard endoscopy to allow the sponge based analysis to be compared with the current test for Barrett s And the researchers analysing the samples from the sponges had no idea whether the sample had come from a patient with Barrett s or not They used the sponge samples to search for the presence of a protein called Trefoil factor 3 TFF3 known to be produced by cells that are becoming gut like and a hallmark of the onset of Barrett s a bit like looking for evidence of the bricks and mortar of the lava proof house to return to our earlier analogy The results of this analysis presented at this year s NCRI Cancer Research Conference showed that not only is the Cytosponge preferred by patients over other methods but crucially that it is able to accurately diagnose Barrett s oesophagus just as well as an endoscopy So what next The team are now aiming to identify which patients with Barrett s oesophagus are more likely to develop cancer by looking for tell tale markers in the cells captured by the sponge such as known cancer related red flags like mutations in the p53 gene which seem to occur as Barrett s develops into oesophageal cancer As with many challenges faced by cancer researchers progress is slow and incremental These are just the first of what we hope to be a string of interesting results from this trial There are almost certainly going to be challenges ahead But smarter thinking like the Cytosponge will help us to diagnose these cancers sooner Emily Hoggar is a science communications manager at Cancer Research UK Share this article More on this topic Tags Cancer Research UK funded research Clinical trials Diagnosing cancer Early detection Oesophageal cancer Research and trials Comments Click here to cancel reply Angela Deighton December 9 2014 Very informative and clear video demonstration Very encouraging to know this test is available miss elizabeth mccann December 8 2014 could I have this test done Margaret Barwell December 6 2014 Great to hear about the sponge test and the promising improvements in patient experience achieved without compromising diagnostic accuracy Would a screening programme such as the cervical smear programme be appropriate and if so is it affordable with the sponge sampling technique Carole coote December 6 2014 As someone who has had

    Original URL path: http://scienceblog.cancerresearchuk.org/2014/12/02/more-progress-in-detecting-oesophageal-cancer-early/ (2016-02-11)
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  • A new age of cancer classification and treatment - Cancer Research UK - Science blog
    of the body can be driven by the same genetic engine If a tumour had lots of somatic changes it was almost certain to have very few copy number changes and vice versa This unexpected trend could give insight into the fundamental processes behind how different types of cancer develop And within the two broad groups tumours clustered into subgroups according to their shared genetic signature For example a type of lung cancer shared characteristics with a previously unrelated type of head and neck cancer The broad message from the publications coming out of the Pan Cancer project is clear just as two different models of car can be the same under the hood tumours originating in different parts of the body can be driven by the same genetic engine The wider picture transcending tissue But what does this mean for cancer patients Huge genetic projects aren t merely an intricate exercise in biological stamp collecting the more we understand about the shared characteristics of seemingly different cancers the better equipped we are to treat them Many of the buzzwords of cancer research at the moment such as precision medicine and personalised treatment stem from a growing ambition to treat cancer not just by where it appears in the body but according to its molecular make up For some cancers we re already doing this For example the drug Glivec which has been hailed as a magic bullet for chronic myeloid leukaemia was designed to work in patients with a particular genetic fault And the widely used breast cancer treatment Herceptin is given to women with a particular subtype of the disease that has an overabundance of a protein called HER2 Interestingly Herceptin isn t targeted at breast cancer as such but targets cancer cells that produce too much of HER2 As a result it s since been found to work in other HER2 containing cancer types such as stomach cancer Old dog new tricks But beside some very noteworthy successes scientists have so far struggled to bring the promise of truly personalised treatment to the majority of cancer patients This could change in the coming years Massive projects such as the Pan Cancer Initiative apply the logic of molecular based tumour classification on a much larger scale and are helping researchers pinpoint similarities between different tumour types that have been missed by smaller studies One result is that we re finding already available drugs could be used in different types of cancer as well as discovering new molecular weaknesses in cancer that we can exploit Our work Clinical trials 2 0 Another implication of such large scale molecular fingerprinting studies is that the way clinical trials are designed in future needs careful thought Our scientists are pioneering the design of ever more sophisticated clinical trials that take into account the molecular differences between tumours of the same cancer type For example Professor Tim Maughan in Oxford is running a flagship clinical trial for bowel cancer patients that will give

    Original URL path: http://scienceblog.cancerresearchuk.org/2013/10/15/a-new-age-of-cancer-classification-and-treatment/ (2016-02-11)
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