tag:theconversation.com,2011:/us/topics/leukeamia-9101/articlesleukeamia – The Conversation2019-02-12T07:57:44Ztag:theconversation.com,2011:article/1105362019-02-12T07:57:44Z2019-02-12T07:57:44ZCancer: new DNA sequencing technique analyses tumours cell by cell to fight disease<figure><img src="https://images.theconversation.com/files/258215/original/file-20190211-174861-59dmgg.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Illustration of acute lymphoblastic leukaemia,
showing lymphoblasts in blood.</span> <span class="attribution"><a class="source" href="https://www.shutterstock.com/image-illustration/acute-lymphoblastic-leukemia-3d-illustration-showing-1245396199">Kateryna Kon/Shutterstock</a></span></figcaption></figure><p>A new DNA sequencing technique lets scientists track genetic errors in individual cancer cells. For the first time, they can reconstruct a tumour’s life history and understand how an error in a cell’s DNA led to the uncontrollable growth of a tumour. This new technology will help doctors understand how a particular cancer has evolved and personalise treatments for each patient, to make them more effective and successful.</p>
<p>We are made of billions of cells that work together to build every part of our body. Occasionally, one of these cells acquires an error in its genetic code and this error, or mutation, can sometimes make this abnormal single cell divide and grow faster than the healthy ones, causing a tumour to develop. During this process, cells can continue to evolve and accumulate many more mutations that make it more dangerous than the original one.</p>
<p>Previously, when researchers studied cancer, they used to take a piece of the tumour and analyse it as a whole. Without understanding the life history of each tumour, science could only give us an incomplete picture of the cancer, where the different cells are mixed and averaged, to get an idea of how dangerous the cancer was. But it didn’t tell us anything about how the tumour had evolved and what type of cells it was made of, making it hard for doctors to select the right treatment for each patient. </p>
<p>This is the reason many cancer treatments don’t work, and when they do, cancer sometimes regrows within a few months or years, coming back a lot more aggressive than the previous one and much more difficult to treat. </p>
<h2>Seeing the whole picture</h2>
<p>As the entire tumour couldn’t be beaten as a whole, five years ago, researchers started using a different strategy: <a href="http://science.sciencemag.org/content/344/6190/1396">divide and conquer</a>. They began dividing the tumours into single cells and analysing each cancer cell separately to try and understand which types of cells made up each tumour. </p>
<p>But even with this advance, they still only had two main tools to analyse single cancer cells. One tool allowed them to read the genetic code of a single cell at a time, identifying which cells have genetic mutations. The other tool helped them understand which genes were active in each cancerous cell, and what their role in the cells was. However, neither of these tools revealed the whole picture. Using them, you could either get the genetic errors from each cell, or the genes that are active and functional – but not both. This made it impossible to understand which genes are activated as a result of genetic errors in each cell. </p>
<p>A team of researchers at the MRC Weatherall Institute of Molecular Medicine, University of Oxford, developed a new single-cell sequencing technique that allowed them to see the whole picture. It lets scientists analyse the genetic errors that each cell in a tumour has accumulated while also understanding its gene activity and cell function. This will allow researchers to see in fine detail every aspect of the tumour.</p>
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<img alt="" src="https://images.theconversation.com/files/258231/original/file-20190211-174883-1p7a1tr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/258231/original/file-20190211-174883-1p7a1tr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=420&fit=crop&dpr=1 600w, https://images.theconversation.com/files/258231/original/file-20190211-174883-1p7a1tr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=420&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/258231/original/file-20190211-174883-1p7a1tr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=420&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/258231/original/file-20190211-174883-1p7a1tr.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=528&fit=crop&dpr=1 754w, https://images.theconversation.com/files/258231/original/file-20190211-174883-1p7a1tr.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=528&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/258231/original/file-20190211-174883-1p7a1tr.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=528&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px">
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<span class="caption">Researcher Alba Rodriguez-Meira shows a typical plate used in these experiments. Each can hold 384 cancer cells.</span>
<span class="attribution"><span class="source">MRC Weatherall Institute of Molecular Medicine</span>, <span class="license">Author provided</span></span>
</figcaption>
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<p>In their latest study, published in <a href="https://www.cell.com/molecular-cell/fulltext/S1097-2765(19)30009-7">Molecular Cell</a>, they used this new technique, called TARGET-seq, to analyse many thousands of cells from 11 patients whose blood-making cells had become cancerous. Their analysis provided a detailed picture of the cell types that made up blood cancers. Thanks to its high resolution, they could reconstruct the complete life history of each tumour and identify the molecules that were active during the first steps of tumour development. They also found that cells that appeared healthy, as they didn’t have cancerous mutations, were behaving like malignant cells and activating abnormal genes because they were in a tumour environment. </p>
<p>Scientists are now using TARGET-seq to analyse different types of aggressive leukaemias for which there are no effective treatments. They are hoping to understand how to eliminate the cells that started and sustained the tumour, to be able to completely eradicate them. In the future, we hope that this technique will be used by oncologists to determine the exact mixture of cancer cells that makes up each tumour and customise the right treatment for each patient.</p><img src="https://counter.theconversation.com/content/110536/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>Alba Rodriguez-Meira receives funding from Cancer Research UK.</span></em></p><p class="fine-print"><em><span>Adam Mead receives funding from the Medical Research Council (MR/L006340/1) </span></em></p>Seeing cancer in ‘high-resolution’ could improve personalised medicine.Alba Rodriguez-Meira, PhD Student, University of OxfordAdam Mead, Professor of Haematology, University of OxfordLicensed as Creative Commons – attribution, no derivatives.tag:theconversation.com,2011:article/871032017-11-09T05:51:51Z2017-11-09T05:51:51ZWe made great strides with childhood leukaemia – we can do the same for brain cancer<figure><img src="https://images.theconversation.com/files/193732/original/file-20171108-2011-u9y0ti.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=496&fit=clip" /><figcaption><span class="caption">Survival rates for childhood brain cancer have not improved for decades.</span> <span class="attribution"><span class="source">from shutterstock.com</span></span></figcaption></figure><p>Brain cancers are the <a href="https://www.aihw.gov.au/reports/cancer/cancer-in-australia-2017/contents/table-of-contents">leading disease-related cause of death</a> in Australian children. And survival rates have <a href="http://www.curebraincancer.org.au/page/8/facts-stats">changed little</a> in decades. As a paediatric oncologist, the worst conversation I can have with my patients or their parents is to tell them their tumour is incurable.</p>
<p>Last week, the federal government announced the <a href="https://canceraustralia.gov.au/about-us/news/minister-greg-hunt-announces-australian-brain-cancer-mission">Australian Brain Cancer Mission</a>, with a A$100 million injection for research to double survival rates and improve quality of life for people living with brain cancer over the next ten years. This is an important step forward. </p>
<p>My hope is that we can replicate for brain cancer what has been achieved for leukaemia. The survival rate for the most common form of childhood leukaemia was once zero but <a href="https://www.cancer.org/cancer/leukemia-in-children/detection-diagnosis-staging/survival-rates.html">today it’s 85%</a>. To achieve this outcome for brain tumour patients, we will need to adopt a similar strategy as with leukaemia.</p>
<h2>Childhood leukaemia treatment</h2>
<p>In the first half of the last century, parents whose children were diagnosed with leukaemia were told to <a href="http://onlinelibrary.wiley.com/doi/10.1111/jpc.12803/pdf">take them home to die</a>. Then chemotherapy was introduced. In the early 1940s, the first chemotherapy trial in children <a href="http://www.nejm.org/doi/full/10.1056/NEJM194806032382301#t=article">used a drug called aminopterin</a>, which suppresses the immune system. </p>
<p>In November 1947, <a href="http://www.dana-farber.org/about-us/history-and-milestones/sidney-farber,-md/">Dr Sidney Farber</a>, a pathologist at Children’s Hospital in Boston, discovered that the cells that develop into leukaemia grew rapidly when stimulated with the vitamin folate. He then helped develop the drug aminopterin that targets folate metabolism. He tested aminopterin in 16 children with leukaemia and obtained <a href="http://www.nejm.org/doi/full/10.1056/NEJM194806032382301#t=article">temporary remission</a> in ten of them. While this provided a glimmer of hope, it wasn’t a cure. After the treatment stopped, the cancer always came back.</p>
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<a href="https://images.theconversation.com/files/193909/original/file-20171109-11989-9fl29j.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=1000&fit=clip"><img alt="" src="https://images.theconversation.com/files/193909/original/file-20171109-11989-9fl29j.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&fit=clip" srcset="https://images.theconversation.com/files/193909/original/file-20171109-11989-9fl29j.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=600&h=400&fit=crop&dpr=1 600w, https://images.theconversation.com/files/193909/original/file-20171109-11989-9fl29j.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=600&h=400&fit=crop&dpr=2 1200w, https://images.theconversation.com/files/193909/original/file-20171109-11989-9fl29j.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=600&h=400&fit=crop&dpr=3 1800w, https://images.theconversation.com/files/193909/original/file-20171109-11989-9fl29j.jpg?ixlib=rb-1.1.0&q=45&auto=format&w=754&h=503&fit=crop&dpr=1 754w, https://images.theconversation.com/files/193909/original/file-20171109-11989-9fl29j.jpg?ixlib=rb-1.1.0&q=30&auto=format&w=754&h=503&fit=crop&dpr=2 1508w, https://images.theconversation.com/files/193909/original/file-20171109-11989-9fl29j.jpg?ixlib=rb-1.1.0&q=15&auto=format&w=754&h=503&fit=crop&dpr=3 2262w" sizes="(min-width: 1466px) 754px, (max-width: 599px) 100vw, (min-width: 600px) 600px, 237px"></a>
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<span class="caption">Aminopterin has a potent effect on leukaemia cells growing in a test tube.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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<p>A major breakthrough came in 1965 in the US with a combination of four drugs – vincristine, prednisone, methotrexate and 6-mercaptopurine – <a href="https://www.cancer.gov/about-cancer/treatment/drugs/VAMP">known as VAMP</a>. These drugs all have different mechanisms of action and together were shown <a href="https://pdfs.semanticscholar.org/a224/e189e31a73e0df56bdb6ca2b319cd765dd40.pdf">to induce long-term remissions</a> in children with acute lymphoblastic leukaemia (ALL) – the most common form of childhood leukaemia. </p>
<p>Today it is a generally accepted rule of cancer treatment that drugs are more effective in combination than as single agents. In the period 1965-1979, childhood leukaemia <a href="https://jamanetwork.com/journals/jama/fullarticle/392061">death rates in the US fell 50%</a> due to improvements in therapies like this, as well as other ongoing developments. </p>
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Read more:
<a href="https://theconversation.com/explainer-what-is-chemotherapy-and-how-does-it-work-76403">Explainer: what is chemotherapy and how does it work?</a>
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<h2>Leukaemia lessons</h2>
<p>The significant advances in the treatment of paediatric ALL have come, in large part, from the high participation rate of patients in clinical trials. But there are several other lessons that will help in our battle against brain cancer. </p>
<p>First, the initial and crucial discoveries in leukaemia treatments were made in the laboratory, using models that reflected the disease in humans. Until recently, these models have been lacking for paediatric brain tumours. </p>
<p>Second, leukaemia was not cured with any single magic bullet. Combination therapy made a radical difference to success rates. </p>
<p>Today children with leukaemia are cured by using intensive treatment with 10 to 12 different chemotherapeutic agents. Given brain cancer is even more aggressive than leukaemia, it is likely potent combinations will be needed to make a difference in outcomes. </p>
<p>Third, there was a seamless transition from the lab to clinical (human) trials in leukaemia. It was the same researcher running the laboratory who took his or her discoveries and started treating their own patients. </p>
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<p>
<em>
<strong>
Read more:
<a href="https://theconversation.com/childhood-cancer-deaths-have-fallen-in-australia-but-some-types-remain-more-of-a-challenge-61666">Childhood cancer deaths have fallen in Australia, but some types remain more of a challenge</a>
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<h2>Difficulties in brain cancer</h2>
<p>Brain tumours may occur in or near critical areas of the brain. For instance, these areas may control speech, movement or even breathing, making surgery risky or impossible.</p>
<p>The most aggressive cancer in children is a type of brain tumour called Diffuse Intrinsic Pontine Glioma (DIPG), which remains completely incurable. Its sensitive location in the brainstem means the tumour cannot be removed surgically. Even biopsies are usually not performed. </p>
<p>Patients don’t respond to chemotherapy. The <a href="http://dipgregistry.org/patients-families/treatment/">only standard therapy is radiation</a>, which only temporarily delays disease progression. Most children do not survive more than one or two years after diagnosis.</p>
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<span class="caption">Brain cancer is difficult to treat because of the sensitive location of the tumours.</span>
<span class="attribution"><span class="source">from shutterstock.com</span></span>
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<p>Even if drugs can be shown to work in the lab, a major challenge for drug treatments for brain cancers is the blood-brain barrier, a membrane that protects the brain from toxins but also stops access for many anti-cancer drugs. Very few drugs can <a href="https://link.springer.com/article/10.1602%2Fneurorx.2.1.3">make it across the barrier</a> from the bloodstream to reach tumours. In tumours like DIPG, it seems the blood-brain barrier is particularly tight.</p>
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Read more:
<a href="https://theconversation.com/explainer-what-is-the-blood-brain-barrier-and-how-can-we-overcome-it-75454">Explainer: what is the blood-brain barrier and how can we overcome it?</a>
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<h2>What we need to do</h2>
<p>One issue that has hampered medical research into childhood brain cancer treatments is a lack of tissue samples. Farber easily obtained leukaemia cells from the blood of his patients, which was central to making his discoveries. Collecting samples from brain tumour patients is much more risky and until recently had been considered impossible. </p>
<p>To address this my team started a <a href="https://www.frontiersin.org/articles/10.3389/fonc.2017.00057/full">donation program</a> for parents to donate their child’s tumour after a child has died. We are also learning how to safely biopsy DIPG tumours. We have obtained 31 tumour samples to help investigate <a href="https://www.frontiersin.org/articles/10.3389/fonc.2017.00057/full">DIPG’s genetics and biology</a> and to test potential treatments. </p>
<p>This is part of <a href="http://dipgregistry.org/">a global initiative</a> that owes its existence in large part to the generosity of parents wanting to help other families. We have used this resource to screen more than 3,500 drugs, in one of the largest DIPG drug screens. As a result, we have identified five active drugs that cross the blood-brain barrier and have anti-DIPG activity. </p>
<p>We have also performed screens looking at thousands of different drug combinations to identify further active therapeutic strategies. </p>
<p>Funding for brain tumour research will help ensure discoveries made from efforts like this can be rapidly translated to clinical trials to help children who need new treatment options. To achieve this, it is critical that funding goes to support intensive laboratory research, as well as the clinical trial infrastructure needed to bring these discoveries directly to the patients. </p>
<p>Last but not least, personalised medicine holds great hope for children with brain cancer, offering the opportunity to exploit each tumour’s distinctive molecular and genetic features. We have conducted a pilot personalised medicine study for Australian children with high-risk cancers, through the <a href="http://www.zerochildhoodcancer.org.au/">Zero Childhood Cancer</a> program led by the Children’s Cancer Institute and Sydney Children’s Hospital, Randwick. </p>
<p>About half the children in this study had brain tumours – highlighting that this remains a critical area in need of more research and new treatments. </p>
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Read more:
<a href="https://theconversation.com/how-cancer-doctors-use-personalised-medicine-to-target-variations-unique-to-each-tumour-47349">How cancer doctors use personalised medicine to target variations unique to each tumour</a>
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<p>In mid-September, <a href="https://ccia.org.au/children-aggressive-cancers-benefit-from-australian-first-personalised-medicine-clinical-trial/">we opened a national clinical trial</a> that will enrol up to 400 children with high-risk cancers over the next three years. We expect children with brain cancers will be one of the biggest groups of patients on the trial.</p>
<p>We hope the program will not only help individual children but that lessons learnt from the trial will be used to discover and test future treatments for brain cancer, boosting survival further.</p>
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<p><em>This article previously said Dr Sidney Farber observed leukaemia cells in test tubes. This has now been changed.</em></p><img src="https://counter.theconversation.com/content/87103/count.gif" alt="The Conversation" width="1" height="1" />
<p class="fine-print"><em><span>David Ziegler receives funding from the NHMRC, Cancer Institute NSW, Kids Cancer Alliance, Cancer Australia, Benny Wills Brain Tumour Foundation, The Cure Starts Now, The Kids Cancer project, Cure Brain Cancer, Children's Cancer Foundation and Tour de Cure. </span></em></p>Leukaemia used to be a death sentence. Now, the survival rate for the most common form in children is 85%. We can apply similar strategies to how we approach childhood brain cancer.David Ziegler, Associate Professor (conjoint), Children's Cancer InstituteLicensed as Creative Commons – attribution, no derivatives.