Cancer drops sparse chemical hints of its presence early on, but unfortunately, many of them are in a class of biochemicals that could not be detected thoroughly, until now. Researchers at the Georgia Institute of Technology have engineered a chemical trap that exhaustively catches what are called glycoproteins, including minuscule traces that have previously escaped detection. Glycoproteins are protein molecules bonded with sugar molecules, and they’re very common in all living things. Glycoproteins come in myriad varieties and sizes and make up important cell structures like cell receptors. They also wander around our bodies in secretions like mucus or hormones. But some glycoproteins are very, very rare and can serve as an early signal, or biomarker, indicating there’s something wrong in the body – like cancer. Existing methods to reel in glycoproteins for laboratory examination are relatively new and have had big holes in their nets, so many of these molecules, especially those very rare ones produced by cancer, have tended to slip by. “These tiny traces are critically important for early disease detection,” said principal investigator Ronghu Wu, a professor in Georgia Tech’s School of Chemistry and Biochemistry. “When cancer is just getting started, aberrant glycoproteins are produced and secreted into body fluids such as blood and urine. Often their abundances are extremely low, but catching them is urgent.” This new chemical trap, which took Georgia Tech chemists several years to develop and is based on a boronic acid, has proven extremely effective in lab tests including on cultured human cells and mouse tissue samples. “This method is very universal,” said first author Haopeng Xiao, a graduate research assistant. “We get over 1,000 glycoproteins in a really small lab sample.” In comparison tests with existing methods, the chemical trap, a complex molecular construction reminiscent of an octopus, captured exponentially more glycoproteins, especially more of those trace glycoproteins. Wu, Xiao and Weixuan Chen, a former Georgia Tech postdoctoral researcher, who was also first author of the study alongside Xiao. For chemistry whizzes, here’s a short summary of how the researchers made the octopus. They took a good thing and doubled then tripled down on it. Those who recall high school chemistry class may still know what boric acid is, as do people who use it to kill roaches. Its chemical structure is an atom of boron bonded with three hydroxyl groups (H3BO3). Boronic acids are a family of organic compounds that build on boric acid. There are many members of the boronic acid family, and they tend to bond well with glycoproteins, but their bonds can be less reliable than needed. “Most boronic acids let too many low-abundance glycoproteins get away,” Wu said. “They can catch glycoproteins that are in high abundance but not those in low abundance, the ones that tell us more valuable things about cell development or about human disease.” But the Georgia Tech chemists were able to leverage the strengths of boronic acids to develop a glycoprotein capturing method that works exceptionally well. First, they tested several boronic acid derivatives and found that one called benzoboroxole strongly bound with each sugar component on the glycopeptide. (“Peptide” refers to the basic chemical composition of a protein.) Then they stitched many benzoboroxole molecules together with other components to form a "dendrimer," which refers to the resulting branch- or tentacle-like structure. The finished large molecule resembled an octopus ready to go after those sugar components. In its middle, similarly positioned to an octopus’s head, was a magnetic bead, which acted as a kind of handle. Once the dendrimer caught a glycoprotein, the researchers used a magnet to grab the bead and pull out their chemical octopus along with its ensnared glycopeptides (e.g. glycoproteins). “Then we washed the dendrimer off with a low pH solution, and we had the glycoproteins analysed with things like mass spectrometry,” Wu said. The researchers have some ideas about how medical laboratory researchers could make practical use of the new Georgia Tech method to detect odd biomolecules emitted by cancer, such as antigens. For example, the chemical octopus could improve detection of prostate-specific antigens (PSA) in prostate cancer screenings. “PSA is a glycoprotein. Right now, if the level is very high, we know that the patient may have cancer, and if it’s very low, we know cancer is not likely,” Wu said. “But there is a gray area in between, and this method could lead to much more detailed information in that gray area.” The researchers also believe that developers could leverage the chemical invention to produce targeted cancer treatments. Immune cells could be trained to recognize the aberrant glycoproteins, track down their source cancer cells in the body and kill them.
Georgia Institute of Technologywww.news.gatech.edu/2018/05/04/chemical-octopus-catches-sneaky-cancer-clues-trace-glycoproteins
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:41Chemical octopus catches sneaky cancer clues, trace glycoproteins
Researchers have found that UTY, a gene on the Y chromosome, protects male mice lacking the tumour-suppressing UTX gene on the X chromosome from developing acute myeloid leukaemia Researchers at the Wellcome Sanger Institute and the University of Cambridge found that this Y-chromosome gene protects against the development of Acute Myeloid Leukaemia (AML) and other cancers. The study investigated how loss of the X-chromosome gene UTX, which is known to be mutated in many tumours, hastens the development of AML. However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML. The authors then show that in AML and in several other human cancers types, loss of UTX is accompanied by loss of UTY, confirming that the cancer-suppressing role of UTY extends beyond AML. Acute myeloid leukaemia is an aggressive blood cancer that affects people of all ages. It develops in cells in the bone marrow and leads to life-threatening infections and bleeding. Mainstream AML treatments have remained unchanged for decades. Women have two X chromosomes whereas men have one X and one Y chromosome. The X and Y chromosomes share many genes, but a small number of genes, including UTY, are only found on the Y chromosome. These Y-specific genes were thought to contain the genetic information required for male sexual characteristics, but were not known to have other roles. The discovery of this new role changes the way the Y chromosome is viewed and improves understanding of how AML and other cancers develop.
“This is the first Y chromosome-specific gene that protects against AML. Previously it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.” Dr Malgorzata Gozdecka, the first author on the study from the Wellcome Sanger Institute
“It is known that men often lose the Y chromosome from their cells as they age, however the significance of this was unclear. Our study strengthens the argument that loss of the Y chromosome can increase the risk of cancer and describes a mechanism for how this may happen.” Professor Brian Huntly, joint project leader from the Wellcome-MRC Cambridge Stem Cell Institute, and Consultant Haematologist, at Cambridge University Hospitals NHS Trust
In their study, researchers studied the UTX gene in human cells and in mice to try to understand its role in AML. In addition to their discovery that UTY acts as a tumour suppressor gene, the scientists found a new mechanism for how loss of UTX leads to AML. They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY. When UTX/UTY are missing, these proteins can’t regulate gene expression correctly and cancer growth becomes more likely.
“Treatments for AML have not changed in decades and there is a large unmet need for new therapies. This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukaemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.” Dr George Vassiliou, joint project leader from the Wellcome Sanger Institute, Wellcome-MRC Cambridge Stem Cell Institute and Consultant Haematologist at Cambridge University Hospitals NHS Trust.
“Survival rates for AML remain tragically low, with current treatment that involves intensive chemotherapy, often combined with a stem cell transplant, only curing a small proportion of patients. This important research helps build a fuller picture of what goes wrong genetically as this highly aggressive leukaemia develops. Understanding this process is key to developing targeted drugs for AML, allowing us to move away from gruelling and often ineffective chemotherapy-based treatments.”
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:41Leukaemia: protective role of Y chromosone gene discovered
Rates of inherited mutations in genes other than BRCA1/2 are twice as high in breast cancer patients who have had a second primary cancer – including, in some cases, different types of breast cancer – compared to patients who have only had a single breast cancer. But the rates of these mutations were still found to be low overall, meaning it’s difficult to assess whether and how these individual mutations may drive the development of cancer. The study from the Basser Center for BRCA in the Abramson Cancer Center of the University of Pennsylvania also investigated the use of polygenic risk scores – which have recently been added to some commercial clinical multiplex genetic testing panels. Kara N. Maxwell, MD, PhD, an instructor of Hematology-Oncology and the study’s lead author, presented the findings at the 2018 American Society of Clinical Oncology Annual. Genetic testing can help identify patients have a genetic predisposition that puts them at risk for developing cancer. Recently, new therapies called PARP inhibitors have been FDA approved to specifically target cancers caused by certain mutations – such as BRCA1/2, which carry a lifetime breast cancer risk of as much as 85 percent and 50 percent for ovarian cancer, as well as higher risks of pancreatic, prostate and other cancers. “We need to gain a better understanding of why patients who have multiple cancers may be susceptible to them, and that work needs to go beyond the common genes we’re already been looking at,” Maxwell said. The team – led by Susan M. Domchek, MD, executive director of the Basser Center for BRCA, and Katherine L. Nathanson, MD, deputy director of the Abramson Cancer Center, specifically looked at patients who did not have a BRCA1/2 mutation and tested them for a panel of 15 different genetic mutations. They evaluated 891 patients who had a second primary cancer – breast or otherwise – after initial breast cancer and compared them to 1,928 who only had a single breast cancer. About eight percent of patients who had second primary cancers had mutations, compared to just four percent of patients from the single cancer cohort. The current threshold for whether or not genetic testing is recommended is five percent. “Our data show that patients who have had multiple primary cancers should undergo genetic testing, and likely this holds true for a number of other types of second cancer,” Maxwell said. “However, the overall numbers are still low, which shows the level of uncertainty that still exists and highlights the need for further research.” The research also evaluated polygenic risk scores, a somewhat controversial metric recently added to some commercial clinical multiplex genetic testing panels. Polygenic risk scores are determined by how many single nucleotide polymorphisms (SNPs) a person has. SNPs are common variants with smaller effect sizes, and if a patient has multiple of certain SNPs, they may be at a similar increased for cancer a as patients with a single rare mutation. “Our study does not provide strong evidence of higher polygenic risk scores in patients with more than one breast cancer,” but many more patients will need to be studied to confirm this,” Maxwell said.
Penn Medicinewww.pennmedicine.org/news/news-releases/2018/june/beyond-brca-examining-links-between-breast-cancer-second-primary-cancer-inherited-genetic-mutations
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:41Examining links between breast cancer, second primary cancer and inherited genetic mutations
The enzyme Dicer cleaves long precursors into short RNA molecules called microRNAs. A new study reveals how Dicer enhances energy metabolism and reduces levels of fat storage in macrophages, thus slowing the progression of atherosclerosis. Atherosclerosis is one of the primary causes of premature death in modern societies. The condition is characterized by the deposition of fat-soluble molecules – principally cholesterol and triglycerides – on the inner walls of major blood vessels. This process triggers vascular inflammation and the formation of atherosclerotic plaques, which ultimately lead to narrowing of the arteries, thus impeding the flow of blood. Cells called macrophages are responsible for the uptake and disposal of the fatty deposits that induce plaque formation. However, depending on how they have been activated, macrophages can play an insidious role in the development of atherosclerosis. Inflammatory activation promotes inflammation, while ‘alternatively activated’ macrophages suppress inflammation reactions. The latter degrade triglycerides by means of fatty acid oxidation, but if this pathway operates sub-optimally – due to local inflammation, for example – they accumulate the engulfed fats, thus contributing to plaque development and increasing the risk of blood vessel blockage. A team of researchers in the Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases at the LMU Medical Center, led by Professor Andreas Schober, has now shown that the enzyme Dicer plays an important role in the breakdown of triglycerides in alternatively activated macrophages. Dicer slices long precursor RNAs into short snippets, which are known as microRNAs (miRNAs). miRNAs make a significant contribution to the regulation of gene activity. By binding to complementary nucleotide sequences in messenger RNAs (mRNAs), miRNAs prevent the synthesis of specific proteins. The Munich researchers used a mouse model system to study the impact of functional deletion of the Dicer gene in macrophages on energy metabolism. “We found that lack of Dicer in macrophages impairs their capacity for oxidative degradation of triglycerides. As a result, they accumulate more fat and develop into what are called foam cells“, Schober explains. Foam cells die at a higher rate than normal macrophages, which stimulates progression of atherosclerosis. Schober and his colleagues went on to show that the effects of Dicer knockout on macrophage function are attributable to the loss of a single microRNA, named miR-10a, which is required for normal regulation of energy metabolism in these cells, and boosts the oxidative breakdown of the fatty acids in triglycerides. In addition, they identified the relevant target of miR-10a as the mRNA that codes for the ligand-dependent nuclear co-repressor protein (Lcor). “When the interaction between the two RNAs” (which reduces levels of the Lcor protein) “is inhibited, progression of atherosclerosis is accelerated, as in the case of the knockout of Dicer,” says Schober. The discovery of this specific regulation of fatty acid metabolism in macrophages could lead to a novel therapeutic strategy for the treatment of atherosclerosis.
LMU Medical Center www.en.uni-muenchen.de/news/newsarchiv/2018/schober_dicer.html
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:41Dicer cuts down on fats
Patient-derived organoids, hollow spheres of cells cultured from tumours, can quickly and accurately predict how patients with pancreatic cancer respond to a variety of treatments, facilitating a precision-medicine approach to the deadly disease. The ability to use organoids as a treatment tool was investigated by an international team of researchers led by Dr. David Tuveson, M.D., Ph.D., Cold Spring Harbor Laboratory (CSHL) Professor and Chief Scientist for The Lustgarten Foundation. “We’ve identified an approach to prioritize treatment strategies for pancreas cancer patients, with the goal of giving them the best shot at survival and the best shot at a good quality of life,” says Dr. Hervé Tiriac, a researcher in Tuveson’s lab and first author of the paper published today in Cancer Discovery. With only 8 percent of patients surviving 5 years beyond their diagnosis, pancreatic cancer is one of the deadliest cancer types. Currently, surgical removal of the cancerous tissue is the only effective treatment, but because the disease progresses so quickly, only 15 percent of patients are eligible for the procedure. Surgery-ineligible patients can be treated with drugs or chemotherapy, but patient response is highly varied and there is no good method to determine which treatment is best for any given patient. For several years, Tuveson has been honing organoid technology to improve research into the disease. Aside from taking only as little as six weeks to grow, a major advantage of organoids is that they can be derived from patients with even very advanced pancreatic cancer, using tiny biopsies. In this latest development, the Tuveson team generated a library of 66 organoids derived from pancreatic ductal adenocarcinoma (PDAC) tumor specimens at various stages of the disease. The researchers demonstrated that the organoids provide an effective precision-medicine “pharmacotyping,” or drug-testing, pipeline. To do this, “we culture the organoid from the patient’s cancer and then test all possible standard-of-care drugs as well as experimental drugs,” Tiriac explains. The team assessed RNA levels in individual organoids—a way to measure gene activity—to predict the sensitivity of an organoid to the five chemotherapies currently administered to pancreatic cancer patients. They found that three so-called “signatures” of gene activity in the organoids correctly identified patients who had responded well to these drugs. “The signatures should enable physicians to choose the best initial chemotherapy treatment for pancreatic cancer,” Tuveson says. Tuveson and his team plan to further refine the gene signatures through additional experiments, and to test in clinical trials the ability of signatures found in organoids to predict the responses of pancreatic cancer patients.
Cold Spring Harbour Laboratory www.cshl.edu/organoid-profiling-personalizes-treatments-for-pancreatic-cancer/
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:40Organoid profiling personalizes treatments for pancreatic cancer
Genetic mutations in blood cells that have made their way into tumours could be red herrings that mislead physicians looking for genetic changes in tumours that are helping to drive the cancer. This finding is significant because physicians could make misinformed treatment decisions. University of North Carolina Lineberger Comprehensive Cancer Center researchers and colleagues will report findings at the 2018 American Society of Clinical Oncology Annual Meeting on Monday, June 4, that show that blood cell mutations accounted for as many as 8 percent of the mutations identified in large-scale genetic sequencing efforts at two major academic centres. “Next-generation sequencing of solid tumours is intended to identify acquired mutations within tumour tissue,” said the study’s first author Catherine C. Coombs, an associate member of UNC Lineberger and an assistant professor in the UNC School of Medicine Division of Hematology/Oncology. “The identification of acquired mutations in blood cells could lead to errors in interpretation of sequencing results.” For the study, researchers reviewed data from patients with solid tumour cancers who had genetic sequencing tests performed by Foundation Medicine as part of their routine clinical care at the N.C. Cancer Hospital and the Moffitt Cancer Center between 2013 and 2017. They also analysed sequencing results for blood samples. A subset of patients at the N.C. Cancer Hospital had their tumours and their blood sequenced through UNCseq, a genetic sequencing clinical trial run by UNC Lineberger researchers. For patients at Moffitt Cancer Center, they compared Foundation Medicine results to sequencing results from banked blood samples. The researchers analysed the data to identify mutations more commonly seen in blood cells. They found that “clonal haematopoiesis,” which are acquired mutations in blood cells, accounted for 8 percent of the mutations. “The presence of clonal haematopoiesis mutations on next-generation sequencing reports from solid tumour biopsies can confound assay interpretation with the risk of misguided application of targeted therapies,” Coombs said. Researchers say further work must be done to develop standard processes for differentiating mutations that occur in the blood versus the tumour in order to ensure accuracy in the tests for physicians who are using the sequencing results to choose personalized treatments for patients. In addition, the study shows an advantage to “paired” sequencing tests, which evaluate mutations in both the blood and the tumour.
University of North Carolina Lineberger Comprehensive Cancer Center unclineberger.org/news/mutations-could-contaminate-genetic-analyses
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:40Blood mutations could contaminate genetic analyses of tumours
A blood test that measures the presence of heart-specific proteins called troponins is used by emergency clinics to diagnose myocardial infarction in patients with chest pain. For the past few years a newer laboratory method has been used at most hospitals in Sweden that is ten times more sensitive than the conventional troponin test. The high-sensitivity troponin test can discover heart attacks earlier so that treatment can commence, which is thought to improve the patients’ prognosis. "But there is a lack of larger studies examining whether the high-sensitivity troponin test is of any significance for patients with newly diagnosed myocardial infarction in terms of survival or the risk of another heart attack," says study leader Dr. Martin Holzmann, associate professor of epidemiology at Karolinska Institutet’s Department of Medicine in Solna and physician at Karolinska University Hospital. The study included all patients in Sweden who had had their first heart attack between 2009 and 2013. This gave a study population of almost 88,000 patients, 40,000 of whom had been diagnosed using the high-sensitivity troponin test and just over 47,000 using the conventional troponin test. The researchers found that five per cent more myocardial infarctions were being diagnosed in hospitals that used the high-sensitivity troponin test. A year after the heart attack was registered there was no difference in mortality between the two groups, although the number of new heart attacks was lower in the group that had been diagnosed using the high-sensitivity troponin test. "This surprised us," says Dr. Holzmann. "We didn’t think that the more sensitive test would affect the risk of future heart attacks." The use of coronary angiography and balloon angioplasty was 16 and 13 per cent more common, respectively in the patients diagnosed with the high-sensitivity troponin test. In the USA, where the new test was not approved until 2017, there are fears that the more sensitive methods can entail a large increase in the number of examinations with no benefit to the patients. "The increase we observed in our study was less than expected, which means that the high-sensitivity troponin test has enabled doctors to single out the patients who benefit from such intervention. We found no differences in medication between the two groups, so the differences in prognosis with fewer new heart attacks could be attributed to the fact that more coronary angiography and balloon dilation procedures have been performed on the right patients," says Dr. Holzmann, who also believes that the study supports the idea that the handful of hospitals in Sweden that still do not use the high-sensitivity troponin test should start to do so.
New findings from the groundbreaking Trial Assigning Individualized Options for Treatment (Rx), or TAILORx trial, show no benefit from chemotherapy for 70 percent of women with the most common type of breast cancer. The study found that for women with hormone receptor (HR)-positive, HER2-negative, axillary lymph node-negative breast cancer, treatment with chemotherapy and hormone therapy after surgery is not more beneficial than treatment with hormone therapy alone. The new data will help inform treatment decisions for many women with early-stage breast cancer. The trial was supported by the National Cancer Institute (NCI), part of the National Institutes of Health, and designed and led by the ECOG-ACRIN Cancer Research Group. “The new results from TAILORx give clinicians high-quality data to inform personalized treatment recommendations for women,” said lead author Joseph A. Sparano, M.D., associate director for clinical research at the Albert Einstein Cancer Center and Montefiore Health System in New York City and vice chair of the ECOG-ACRIN Cancer Research Group. “These data confirm that using a 21-gene expression test to assess the risk of cancer recurrence can spare women unnecessary treatment if the test indicates that chemotherapy is not likely to provide benefit.” TAILORx, a phase 3 clinical trial, opened in 2006 and was designed to provide an evidence-based answer to the question of whether hormone therapy alone is not inferior to hormone therapy plus chemotherapy. The trial used a molecular test (Oncotype DX Breast Recurrence Score) that assesses the expression of 21 genes associated with breast cancer recurrence to assign women with early-stage, HR- positive, HER2-negative, axillary lymph node–negative breast cancer to the most appropriate and effective post-operative treatment. The trial enrolled 10,273 women with this type of breast cancer at 1,182 sites in the United States, Australia, Canada, Ireland, New Zealand, and Peru. When patients enrolled in the trial, their tumours were analysed using the 21-gene expression test and assigned a risk score (on a scale of 0–100) for cancer recurrence. Based on evidence from earlier trials, women in the trial who had a score in the low-risk range (0–10) received hormone therapy only, and those who had a score in the high-risk range (26 and above) were treated with hormone therapy and chemotherapy. Women in the trial who had a score in the intermediate range (11–25) were randomly assigned to receive hormone therapy alone or hormone therapy with adjuvant chemotherapy. The goal was to assess whether women who received hormone therapy alone had outcomes that were as good as those among women who received chemotherapy in addition to hormone therapy. “Until now, we’ve been able to recommend treatment for women with these cancers at high and low risk of recurrence, but women at intermediate risk have been uncertain about the appropriate strategy to take,” said Jeffrey Abrams, M.D., associate director of NCI’s Cancer Therapy Evaluation Program. “These findings, showing no benefit from receiving chemotherapy plus hormone therapy for most patients in this intermediate-risk group, will go a long way to support oncologists and patients in decisions about the best course of treatment.” The researchers found that the primary endpoint of the trial, invasive disease-free survival—the proportion of women who had not died or developed a recurrence or a second primary cancer—was very similar in both groups. Five years after treatment, the rate of invasive disease-free survival was 92.8 percent for those who had hormone therapy alone and 93.1 percent for those who also had chemotherapy. At nine years, the rate was 83.3 percent for those with hormone therapy alone and 84.3 percent for the group that had both therapies. None of these differences were considered statistically significant. The rates of overall survival were also very similar in the two groups. At five years, the overall survival rate was 98.0 percent for those who received hormone therapy alone and 98.1 percent for those who received both therapies, and at nine years the respective overall survival rates were 93.9 percent and 93.8 percent. The researchers also found that women with a score of 0–10 had very low recurrence rates with hormone therapy alone at nine years (3 percent). This confirms similar findings from earlier studies. In addition, they found that women with a score of 26–100 had a distant recurrence rate of 13 percent despite receiving both chemotherapy and hormone therapy. This finding indicates the need to develop more effective therapies for women at high risk of recurrence.
ECOG-ACRIN Cancer Research Group ecog-acrin.org/news-and-info/press-releases/tailorx-trial-finds-most-women-with-early-breast-cancer-do-not-benefit-from-chemotherapy
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:40TAILORx trial finds most women with early breast cancer do not benefit from chemotherapy
In a new study researchers from the Institute for Experimental Pediatric Endocrinology of the Charité – Universitätsmedizin Berlin have successfully treated patients whose obesity is caused by a genetic defect. Aside from its beneficial effects on the patients, the researchers also provided insights into the fundamental signalling pathways regulating satiety of the new drug.
A mutation in the gene encoding the leptin receptor (LEPR) can cause extreme hunger starting with the first months of life. As a result, affected individuals develop extreme obesity during childhood. Increased exercise and reduced caloric intake are usually insufficient to stabilize body-weight. In many cases, obesity surgery fails to deliver any benefits, meaning that a drug-based treatment approach becomes increasingly important.
Two years ago, Dr. Peter Kühnen and the working group successfully demonstrated that treatment with a peptide, which activates the melanocortin 4 receptor (MC4R) could play a central role in the body’s energy metabolism and body weight regulation. Leptin, which is also known as the satiety (or starvation) hormone, normally binds to the LEPR, triggering a series of steps that leads to the production of melanocytestimulating hormone (MSH). The binding of MSH to its receptor, the melanocortin 4 receptor (MC4R) transduces the satiety signal to the body. However, if LEPR is defective, the signalling cascade is interrupted. The patient’s hunger remains unabated, placing her/him at greater risk of becoming obese. As part of this current study, researchers used a peptide that binds to the MC4R in the brain, and this activation triggers the normal satiety signal. Working in cooperation with the Clinical Research Unit at the Berlin Institute of Health (BIH), the researchers were able to record significant weight loss in patients with genetic defects affecting LEPR.
“We also wanted to determine why the used peptide was so effective and why, in contrast to other preparations with a similar mode of action, it did not produce any severe side effects,” explains Dr. Kühnen. “We were able to demonstrate that this treatment leads to the activation of a specific and important signalling pathway, whose significance had previously been underestimated.” Dr. Kühnen’s team is planning to conduct further research to determine whether other patients might benefit from this drug: “It is possible that other groups of patients with dysfunctions affecting the same signalling pathway might be suitable candidates for this treatment.”
Charité – Universitätsmedizin Berlin https://tinyurl.com/y7dyaqm4
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:39A new drug to help young patients with genetic obesity
Scientists have known for decades that the Hox family of transcription factors are key regulators in the formation of blood cells and the development of leukemia. Exactly how this large family of genes, which are distributed in four separate chromosomal clusters named A through D, is regulated has been less clear. Now, new research from the Stowers Institute for Medical Research reveals that a DNA regulatory element within the Hoxb cluster globally mediates signals to the majority of Hoxb genes to control their expression in blood-forming stem cells. “It’s like we found a general control that simultaneously turns the lights on and off in many rooms, rather than having a single switch that controls each individual room,” says Stowers Investigator Linheng Li, PhD, who co-led the study along with Stowers Scientific Director and Investigator Robb Krumlauf, PhD. These findings also help explain why a particular form of leukemia resists treatment and points to potential new therapeutic avenues. In mammals, the blood system contains a number of mature cell types — white blood cells, red blood cells, platelets — that arise from blood-forming, or hematopoietic, stem cells (HSCs). HSCs renew themselves and differentiate into other cells to replenish the body’s blood supply in a process called hematopoiesis. Hox genes, which are well known for their roles in establishing the body plan of developing organisms, are also important for HSCs to maintain their critical balancing act in the adult blood system, and have been implicated in the development of leukemia. In an article Li, Krumlauf, and co-authors including first author Pengxu Qian, PhD, second author Bony De Kumar, PhD, and other collaborators provide new details as to how Hox genes are regulated in HSCs. They report that a single cis-regulatory element, DERARE, works over a long range to control the majority of Hoxb genes in HSCs in a coordinated manner. The researchers found that the loss of the DERARE decreased Hoxb expression and altered the types of blood cells arising from HSCs, whereas “turning on” DERARE allowed Hoxb cluster gene expression in progenitor cells and increased the progression of leukemia. Genes can be regulated by non-coding DNA sequences termed cis-regulatory sequences. These sequences get input from multiple types of molecules, such as transcription factors, histone modifiers, or various morphogens. The DERARE, or distal element RARE (retinoic acid response element), is a cis-regulatory element that responds to signals from the vitamin A derivative retinoic acid and determines the fate of HSCs. Using human leukemia cell lines and mouse models, the Stowers researchers and collaborators have identified a mechanism for how the retinoid-sensitive DERARE maintains normal hematopoiesis and prevents acute myeloid leukemia (AML) by regulating Hoxb cluster genes in a methylation-dependent manner. Methylation is the process of adding methyl groups to the DNA molecule, which can change the activity of the DNA segment. The researchers demonstrated that DNA methyltransferases mediate DNA methylation on DERARE, leading to reduced Hoxb cluster expression. AML patients with mutations in the DNA methyltransferase DNMT3A exhibit reduced DERARE methylation, elevated Hoxb expression, and adverse outcomes. “In two human AML cell lines carrying a DNMT3A mutation, we used an adaptation of genome editing technology called dCas9-DNMT3A to specifically increase the DNA methylation on DERARE. This targeted methylation technique was able to reduce Hoxb cluster expression and alleviate the progression of leukemia,” says Qian. “It is known that Hoxb cluster genes show a dramatic increase in expression in patients with DNMT3A-mutated AML. Our work provides mechanistic insights into the use of DNA methylation on the DERARE as a potential screening tool for therapeutic drugs that target DNMT3A-mutated AML, thus leading to the development of new drugs for treating AML, in which DNA methylation is abnormal.”
Stowers Institutehttps://tinyurl.com/yarf3xfd
https://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png003wmediahttps://clinlabint.com/wp-content/uploads/sites/2/2020/06/clinlab-logo.png3wmedia2020-08-26 09:32:182021-01-08 11:08:39How epigenetic regulation of the Hoxb gene cluster maintains normal blood-forming cells and inhibits leukemia
We may ask you to place cookies on your device. We use cookies to let us know when you visit our websites, how you interact with us, to enrich your user experience and to customise your relationship with our website.
Click on the different sections for more information. You can also change some of your preferences. Please note that blocking some types of cookies may affect your experience on our websites and the services we can provide.
Essential Website Cookies
These cookies are strictly necessary to provide you with services available through our website and to use some of its features.
Because these cookies are strictly necessary to provide the website, refusing them will affect the functioning of our site. You can always block or delete cookies by changing your browser settings and block all cookies on this website forcibly. But this will always ask you to accept/refuse cookies when you visit our site again.
We fully respect if you want to refuse cookies, but to avoid asking you each time again to kindly allow us to store a cookie for that purpose. You are always free to unsubscribe or other cookies to get a better experience. If you refuse cookies, we will delete all cookies set in our domain.
We provide you with a list of cookies stored on your computer in our domain, so that you can check what we have stored. For security reasons, we cannot display or modify cookies from other domains. You can check these in your browser's security settings.
.
Google Analytics Cookies
These cookies collect information that is used in aggregate form to help us understand how our website is used or how effective our marketing campaigns are, or to help us customise our website and application for you to improve your experience.
If you do not want us to track your visit to our site, you can disable this in your browser here:
.
Other external services
We also use various external services such as Google Webfonts, Google Maps and external video providers. Since these providers may collect personal data such as your IP address, you can block them here. Please note that this may significantly reduce the functionality and appearance of our site. Changes will only be effective once you reload the page
Google Webfont Settings:
Google Maps Settings:
Google reCaptcha settings:
Vimeo and Youtube videos embedding:
.
Privacy Beleid
U kunt meer lezen over onze cookies en privacy-instellingen op onze Privacybeleid-pagina.
Chemical octopus catches sneaky cancer clues, trace glycoproteins
, /in E-News /by 3wmediaCancer drops sparse chemical hints of its presence early on, but unfortunately, many of them are in a class of biochemicals that could not be detected thoroughly, until now.
Researchers at the Georgia Institute of Technology have engineered a chemical trap that exhaustively catches what are called glycoproteins, including minuscule traces that have previously escaped detection.
Glycoproteins are protein molecules bonded with sugar molecules, and they’re very common in all living things. Glycoproteins come in myriad varieties and sizes and make up important cell structures like cell receptors. They also wander around our bodies in secretions like mucus or hormones.
But some glycoproteins are very, very rare and can serve as an early signal, or biomarker, indicating there’s something wrong in the body – like cancer. Existing methods to reel in glycoproteins for laboratory examination are relatively new and have had big holes in their nets, so many of these molecules, especially those very rare ones produced by cancer, have tended to slip by.
“These tiny traces are critically important for early disease detection,” said principal investigator Ronghu Wu, a professor in Georgia Tech’s School of Chemistry and Biochemistry. “When cancer is just getting started, aberrant glycoproteins are produced and secreted into body fluids such as blood and urine. Often their abundances are extremely low, but catching them is urgent.”
This new chemical trap, which took Georgia Tech chemists several years to develop and is based on a boronic acid, has proven extremely effective in lab tests including on cultured human cells and mouse tissue samples.
“This method is very universal,” said first author Haopeng Xiao, a graduate research assistant. “We get over 1,000 glycoproteins in a really small lab sample.”
In comparison tests with existing methods, the chemical trap, a complex molecular construction reminiscent of an octopus, captured exponentially more glycoproteins, especially more of those trace glycoproteins.
Wu, Xiao and Weixuan Chen, a former Georgia Tech postdoctoral researcher, who was also first author of the study alongside Xiao.
For chemistry whizzes, here’s a short summary of how the researchers made the octopus. They took a good thing and doubled then tripled down on it.
Those who recall high school chemistry class may still know what boric acid is, as do people who use it to kill roaches. Its chemical structure is an atom of boron bonded with three hydroxyl groups (H3BO3).
Boronic acids are a family of organic compounds that build on boric acid. There are many members of the boronic acid family, and they tend to bond well with glycoproteins, but their bonds can be less reliable than needed.
“Most boronic acids let too many low-abundance glycoproteins get away,” Wu said. “They can catch glycoproteins that are in high abundance but not those in low abundance, the ones that tell us more valuable things about cell development or about human disease.”
But the Georgia Tech chemists were able to leverage the strengths of boronic acids to develop a glycoprotein capturing method that works exceptionally well.
First, they tested several boronic acid derivatives and found that one called benzoboroxole strongly bound with each sugar component on the glycopeptide. (“Peptide” refers to the basic chemical composition of a protein.)
Then they stitched many benzoboroxole molecules together with other components to form a "dendrimer," which refers to the resulting branch- or tentacle-like structure. The finished large molecule resembled an octopus ready to go after those sugar components.
In its middle, similarly positioned to an octopus’s head, was a magnetic bead, which acted as a kind of handle. Once the dendrimer caught a glycoprotein, the researchers used a magnet to grab the bead and pull out their chemical octopus along with its ensnared glycopeptides (e.g. glycoproteins).
“Then we washed the dendrimer off with a low pH solution, and we had the glycoproteins analysed with things like mass spectrometry,” Wu said.
The researchers have some ideas about how medical laboratory researchers could make practical use of the new Georgia Tech method to detect odd biomolecules emitted by cancer, such as antigens. For example, the chemical octopus could improve detection of prostate-specific antigens (PSA) in prostate cancer screenings.
“PSA is a glycoprotein. Right now, if the level is very high, we know that the patient may have cancer, and if it’s very low, we know cancer is not likely,” Wu said. “But there is a gray area in between, and this method could lead to much more detailed information in that gray area.”
The researchers also believe that developers could leverage the chemical invention to produce targeted cancer treatments. Immune cells could be trained to recognize the aberrant glycoproteins, track down their source cancer cells in the body and kill them.
Georgia Institute of Technologywww.news.gatech.edu/2018/05/04/chemical-octopus-catches-sneaky-cancer-clues-trace-glycoproteins
Leukaemia: protective role of Y chromosone gene discovered
, /in E-News /by 3wmediaResearchers have found that UTY, a gene on the Y chromosome, protects male mice lacking the tumour-suppressing UTX gene on the X chromosome from developing acute myeloid leukaemia
Researchers at the Wellcome Sanger Institute and the University of Cambridge found that this Y-chromosome gene protects against the development of Acute Myeloid Leukaemia (AML) and other cancers.
The study investigated how loss of the X-chromosome gene UTX, which is known to be mutated in many tumours, hastens the development of AML. However, they found that UTY, a related gene on the Y chromosome, protected male mice lacking UTX from developing AML. The authors then show that in AML and in several other human cancers types, loss of UTX is accompanied by loss of UTY, confirming that the cancer-suppressing role of UTY extends beyond AML.
Acute myeloid leukaemia is an aggressive blood cancer that affects people of all ages. It develops in cells in the bone marrow and leads to life-threatening infections and bleeding. Mainstream AML treatments have remained unchanged for decades.
Women have two X chromosomes whereas men have one X and one Y chromosome. The X and Y chromosomes share many genes, but a small number of genes, including UTY, are only found on the Y chromosome. These Y-specific genes were thought to contain the genetic information required for male sexual characteristics, but were not known to have other roles. The discovery of this new role changes the way the Y chromosome is viewed and improves understanding of how AML and other cancers develop.
“This is the first Y chromosome-specific gene that protects against AML. Previously it had been suggested that the only function of the Y chromosome is in creating male sexual characteristics, but our results indicate that the Y chromosome could also protect against AML and other cancers.”
Dr Malgorzata Gozdecka, the first author on the study from the Wellcome Sanger Institute
“It is known that men often lose the Y chromosome from their cells as they age, however the significance of this was unclear. Our study strengthens the argument that loss of the Y chromosome can increase the risk of cancer and describes a mechanism for how this may happen.”
Professor Brian Huntly, joint project leader from the Wellcome-MRC Cambridge Stem Cell Institute, and Consultant Haematologist, at Cambridge University Hospitals NHS Trust
In their study, researchers studied the UTX gene in human cells and in mice to try to understand its role in AML. In addition to their discovery that UTY acts as a tumour suppressor gene, the scientists found a new mechanism for how loss of UTX leads to AML. They discovered that UTX acts as a common scaffold, bringing together a large number of regulatory proteins that control access to DNA and gene expression, a function that can also be carried out by UTY. When UTX/UTY are missing, these proteins can’t regulate gene expression correctly and cancer growth becomes more likely.
“Treatments for AML have not changed in decades and there is a large unmet need for new therapies. This study helps us understand the development of AML and gives us clues for developing new drug targets to disrupt leukaemia-causing processes. We hope this study will enable new lines of research for the development of previously unforeseen treatments and improve the lives of patients with AML.”
Dr George Vassiliou, joint project leader from the Wellcome Sanger Institute, Wellcome-MRC Cambridge Stem Cell Institute and Consultant Haematologist at Cambridge University Hospitals NHS Trust.
“Survival rates for AML remain tragically low, with current treatment that involves intensive chemotherapy, often combined with a stem cell transplant, only curing a small proportion of patients. This important research helps build a fuller picture of what goes wrong genetically as this highly aggressive leukaemia develops. Understanding this process is key to developing targeted drugs for AML, allowing us to move away from gruelling and often ineffective chemotherapy-based treatments.”
Wellcome Sanger Institutewww.sanger.ac.uk/news/view/leukaemia-protective-role-y-chromosone-gene-discovered
Examining links between breast cancer, second primary cancer and inherited genetic mutations
, /in E-News /by 3wmediaRates of inherited mutations in genes other than BRCA1/2 are twice as high in breast cancer patients who have had a second primary cancer – including, in some cases, different types of breast cancer – compared to patients who have only had a single breast cancer. But the rates of these mutations were still found to be low overall, meaning it’s difficult to assess whether and how these individual mutations may drive the development of cancer. The study from the Basser Center for BRCA in the Abramson Cancer Center of the University of Pennsylvania also investigated the use of polygenic risk scores – which have recently been added to some commercial clinical multiplex genetic testing panels. Kara N. Maxwell, MD, PhD, an instructor of Hematology-Oncology and the study’s lead author, presented the findings at the 2018 American Society of Clinical Oncology Annual.
Genetic testing can help identify patients have a genetic predisposition that puts them at risk for developing cancer. Recently, new therapies called PARP inhibitors have been FDA approved to specifically target cancers caused by certain mutations – such as BRCA1/2, which carry a lifetime breast cancer risk of as much as 85 percent and 50 percent for ovarian cancer, as well as higher risks of pancreatic, prostate and other cancers.
“We need to gain a better understanding of why patients who have multiple cancers may be susceptible to them, and that work needs to go beyond the common genes we’re already been looking at,” Maxwell said.
The team – led by Susan M. Domchek, MD, executive director of the Basser Center for BRCA, and Katherine L. Nathanson, MD, deputy director of the Abramson Cancer Center, specifically looked at patients who did not have a BRCA1/2 mutation and tested them for a panel of 15 different genetic mutations. They evaluated 891 patients who had a second primary cancer – breast or otherwise – after initial breast cancer and compared them to 1,928 who only had a single breast cancer. About eight percent of patients who had second primary cancers had mutations, compared to just four percent of patients from the single cancer cohort. The current threshold for whether or not genetic testing is recommended is five percent.
“Our data show that patients who have had multiple primary cancers should undergo genetic testing, and likely this holds true for a number of other types of second cancer,” Maxwell said. “However, the overall numbers are still low, which shows the level of uncertainty that still exists and highlights the need for further research.”
The research also evaluated polygenic risk scores, a somewhat controversial metric recently added to some commercial clinical multiplex genetic testing panels. Polygenic risk scores are determined by how many single nucleotide polymorphisms (SNPs) a person has. SNPs are common variants with smaller effect sizes, and if a patient has multiple of certain SNPs, they may be at a similar increased for cancer a as patients with a single rare mutation.
“Our study does not provide strong evidence of higher polygenic risk scores in patients with more than one breast cancer,” but many more patients will need to be studied to confirm this,” Maxwell said.
Penn Medicinewww.pennmedicine.org/news/news-releases/2018/june/beyond-brca-examining-links-between-breast-cancer-second-primary-cancer-inherited-genetic-mutations
Dicer cuts down on fats
, /in E-News /by 3wmediaThe enzyme Dicer cleaves long precursors into short RNA molecules called microRNAs. A new study reveals how Dicer enhances energy metabolism and reduces levels of fat storage in macrophages, thus slowing the progression of atherosclerosis.
Atherosclerosis is one of the primary causes of premature death in modern societies. The condition is characterized by the deposition of fat-soluble molecules – principally cholesterol and triglycerides – on the inner walls of major blood vessels. This process triggers vascular inflammation and the formation of atherosclerotic plaques, which ultimately lead to narrowing of the arteries, thus impeding the flow of blood. Cells called macrophages are responsible for the uptake and disposal of the fatty deposits that induce plaque formation. However, depending on how they have been activated, macrophages can play an insidious role in the development of atherosclerosis. Inflammatory activation promotes inflammation, while ‘alternatively activated’ macrophages suppress inflammation reactions. The latter degrade triglycerides by means of fatty acid oxidation, but if this pathway operates sub-optimally – due to local inflammation, for example – they accumulate the engulfed fats, thus contributing to plaque development and increasing the risk of blood vessel blockage. A team of researchers in the Institute for Prophylaxis and Epidemiology of Cardiovascular Diseases at the LMU Medical Center, led by Professor Andreas Schober, has now shown that the enzyme Dicer plays an important role in the breakdown of triglycerides in alternatively activated macrophages.
Dicer slices long precursor RNAs into short snippets, which are known as microRNAs (miRNAs). miRNAs make a significant contribution to the regulation of gene activity. By binding to complementary nucleotide sequences in messenger RNAs (mRNAs), miRNAs prevent the synthesis of specific proteins. The Munich researchers used a mouse model system to study the impact of functional deletion of the Dicer gene in macrophages on energy metabolism. “We found that lack of Dicer in macrophages impairs their capacity for oxidative degradation of triglycerides. As a result, they accumulate more fat and develop into what are called foam cells“, Schober explains. Foam cells die at a higher rate than normal macrophages, which stimulates progression of atherosclerosis.
Schober and his colleagues went on to show that the effects of Dicer knockout on macrophage function are attributable to the loss of a single microRNA, named miR-10a, which is required for normal regulation of energy metabolism in these cells, and boosts the oxidative breakdown of the fatty acids in triglycerides. In addition, they identified the relevant target of miR-10a as the mRNA that codes for the ligand-dependent nuclear co-repressor protein (Lcor). “When the interaction between the two RNAs” (which reduces levels of the Lcor protein) “is inhibited, progression of atherosclerosis is accelerated, as in the case of the knockout of Dicer,” says Schober.
The discovery of this specific regulation of fatty acid metabolism in macrophages could lead to a novel therapeutic strategy for the treatment of atherosclerosis.
LMU Medical Center
www.en.uni-muenchen.de/news/newsarchiv/2018/schober_dicer.html
Organoid profiling personalizes treatments for pancreatic cancer
, /in E-News /by 3wmediaPatient-derived organoids, hollow spheres of cells cultured from tumours, can quickly and accurately predict how patients with pancreatic cancer respond to a variety of treatments, facilitating a precision-medicine approach to the deadly disease. The ability to use organoids as a treatment tool was investigated by an international team of researchers led by Dr. David Tuveson, M.D., Ph.D., Cold Spring Harbor Laboratory (CSHL) Professor and Chief Scientist for The Lustgarten Foundation.
“We’ve identified an approach to prioritize treatment strategies for pancreas cancer patients, with the goal of giving them the best shot at survival and the best shot at a good quality of life,” says Dr. Hervé Tiriac, a researcher in Tuveson’s lab and first author of the paper published today in Cancer Discovery.
With only 8 percent of patients surviving 5 years beyond their diagnosis, pancreatic cancer is one of the deadliest cancer types. Currently, surgical removal of the cancerous tissue is the only effective treatment, but because the disease progresses so quickly, only 15 percent of patients are eligible for the procedure. Surgery-ineligible patients can be treated with drugs or chemotherapy, but patient response is highly varied and there is no good method to determine which treatment is best for any given patient.
For several years, Tuveson has been honing organoid technology to improve research into the disease. Aside from taking only as little as six weeks to grow, a major advantage of organoids is that they can be derived from patients with even very advanced pancreatic cancer, using tiny biopsies.
In this latest development, the Tuveson team generated a library of 66 organoids derived from pancreatic ductal adenocarcinoma (PDAC) tumor specimens at various stages of the disease. The researchers demonstrated that the organoids provide an effective precision-medicine “pharmacotyping,” or drug-testing, pipeline. To do this, “we culture the organoid from the patient’s cancer and then test all possible standard-of-care drugs as well as experimental drugs,” Tiriac explains.
The team assessed RNA levels in individual organoids—a way to measure gene activity—to predict the sensitivity of an organoid to the five chemotherapies currently administered to pancreatic cancer patients. They found that three so-called “signatures” of gene activity in the organoids correctly identified patients who had responded well to these drugs. “The signatures should enable physicians to choose the best initial chemotherapy treatment for pancreatic cancer,” Tuveson says.
Tuveson and his team plan to further refine the gene signatures through additional experiments, and to test in clinical trials the ability of signatures found in organoids to predict the responses of pancreatic cancer patients.
Cold Spring Harbour Laboratory
www.cshl.edu/organoid-profiling-personalizes-treatments-for-pancreatic-cancer/
Blood mutations could contaminate genetic analyses of tumours
, /in E-News /by 3wmediaGenetic mutations in blood cells that have made their way into tumours could be red herrings that mislead physicians looking for genetic changes in tumours that are helping to drive the cancer. This finding is significant because physicians could make misinformed treatment decisions.
University of North Carolina Lineberger Comprehensive Cancer Center researchers and colleagues will report findings at the 2018 American Society of Clinical Oncology Annual Meeting on Monday, June 4, that show that blood cell mutations accounted for as many as 8 percent of the mutations identified in large-scale genetic sequencing efforts at two major academic centres.
“Next-generation sequencing of solid tumours is intended to identify acquired mutations within tumour tissue,” said the study’s first author Catherine C. Coombs, an associate member of UNC Lineberger and an assistant professor in the UNC School of Medicine Division of Hematology/Oncology. “The identification of acquired mutations in blood cells could lead to errors in interpretation of sequencing results.”
For the study, researchers reviewed data from patients with solid tumour cancers who had genetic sequencing tests performed by Foundation Medicine as part of their routine clinical care at the N.C. Cancer Hospital and the Moffitt Cancer Center between 2013 and 2017. They also analysed sequencing results for blood samples. A subset of patients at the N.C. Cancer Hospital had their tumours and their blood sequenced through UNCseq, a genetic sequencing clinical trial run by UNC Lineberger researchers. For patients at Moffitt Cancer Center, they compared Foundation Medicine results to sequencing results from banked blood samples.
The researchers analysed the data to identify mutations more commonly seen in blood cells. They found that “clonal haematopoiesis,” which are acquired mutations in blood cells, accounted for 8 percent of the mutations.
“The presence of clonal haematopoiesis mutations on next-generation sequencing reports from solid tumour biopsies can confound assay interpretation with the risk of misguided application of targeted therapies,” Coombs said.
Researchers say further work must be done to develop standard processes for differentiating mutations that occur in the blood versus the tumour in order to ensure accuracy in the tests for physicians who are using the sequencing results to choose personalized treatments for patients. In addition, the study shows an advantage to “paired” sequencing tests, which evaluate mutations in both the blood and the tumour.
University of North Carolina Lineberger Comprehensive Cancer Center
unclineberger.org/news/mutations-could-contaminate-genetic-analyses
High-sensitivity troponin test reduces risk of future heart attack
, /in E-News /by 3wmediaA blood test that measures the presence of heart-specific proteins called troponins is used by emergency clinics to diagnose myocardial infarction in patients with chest pain. For the past few years a newer laboratory method has been used at most hospitals in Sweden that is ten times more sensitive than the conventional troponin test. The high-sensitivity troponin test can discover heart attacks earlier so that treatment can commence, which is thought to improve the patients’ prognosis.
"But there is a lack of larger studies examining whether the high-sensitivity troponin test is of any significance for patients with newly diagnosed myocardial infarction in terms of survival or the risk of another heart attack," says study leader Dr. Martin Holzmann, associate professor of epidemiology at Karolinska Institutet’s Department of Medicine in Solna and physician at Karolinska University Hospital.
The study included all patients in Sweden who had had their first heart attack between 2009 and 2013. This gave a study population of almost 88,000 patients, 40,000 of whom had been diagnosed using the high-sensitivity troponin test and just over 47,000 using the conventional troponin test.
The researchers found that five per cent more myocardial infarctions were being diagnosed in hospitals that used the high-sensitivity troponin test. A year after the heart attack was registered there was no difference in mortality between the two groups, although the number of new heart attacks was lower in the group that had been diagnosed using the high-sensitivity troponin test.
"This surprised us," says Dr. Holzmann. "We didn’t think that the more sensitive test would affect the risk of future heart attacks."
The use of coronary angiography and balloon angioplasty was 16 and 13 per cent more common, respectively in the patients diagnosed with the high-sensitivity troponin test. In the USA, where the new test was not approved until 2017, there are fears that the more sensitive methods can entail a large increase in the number of examinations with no benefit to the patients.
"The increase we observed in our study was less than expected, which means that the high-sensitivity troponin test has enabled doctors to single out the patients who benefit from such intervention. We found no differences in medication between the two groups, so the differences in prognosis with fewer new heart attacks could be attributed to the fact that more coronary angiography and balloon dilation procedures have been performed on the right patients," says Dr. Holzmann, who also believes that the study supports the idea that the handful of hospitals in Sweden that still do not use the high-sensitivity troponin test should start to do so.
MedicalXpress
medicalxpress.com/news/2018-06-high-sensitivity-troponin-future-heart.html
TAILORx trial finds most women with early breast cancer do not benefit from chemotherapy
, /in E-News /by 3wmediaNew findings from the groundbreaking Trial Assigning Individualized Options for Treatment (Rx), or TAILORx trial, show no benefit from chemotherapy for 70 percent of women with the most common type of breast cancer. The study found that for women with hormone receptor (HR)-positive, HER2-negative, axillary lymph node-negative breast cancer, treatment with chemotherapy and hormone therapy after surgery is not more beneficial than treatment with hormone therapy alone. The new data will help inform treatment decisions for many women with early-stage breast cancer.
The trial was supported by the National Cancer Institute (NCI), part of the National Institutes of Health, and designed and led by the ECOG-ACRIN Cancer Research Group.
“The new results from TAILORx give clinicians high-quality data to inform personalized treatment recommendations for women,” said lead author Joseph A. Sparano, M.D., associate director for clinical research at the Albert Einstein Cancer Center and Montefiore Health System in New York City and vice chair of the ECOG-ACRIN Cancer Research Group. “These data confirm that using a 21-gene expression test to assess the risk of cancer recurrence can spare women unnecessary treatment if the test indicates that chemotherapy is not likely to provide benefit.”
TAILORx, a phase 3 clinical trial, opened in 2006 and was designed to provide an evidence-based answer to the question of whether hormone therapy alone is not inferior to hormone therapy plus chemotherapy. The trial used a molecular test (Oncotype DX Breast Recurrence Score) that assesses the expression of 21 genes associated with breast cancer recurrence to assign women with early-stage, HR- positive, HER2-negative, axillary lymph node–negative breast cancer to the most appropriate and effective post-operative treatment. The trial enrolled 10,273 women with this type of breast cancer at 1,182 sites in the United States, Australia, Canada, Ireland, New Zealand, and Peru.
When patients enrolled in the trial, their tumours were analysed using the 21-gene expression test and assigned a risk score (on a scale of 0–100) for cancer recurrence. Based on evidence from earlier trials, women in the trial who had a score in the low-risk range (0–10) received hormone therapy only, and those who had a score in the high-risk range (26 and above) were treated with hormone therapy and chemotherapy.
Women in the trial who had a score in the intermediate range (11–25) were randomly assigned to receive hormone therapy alone or hormone therapy with adjuvant chemotherapy. The goal was to assess whether women who received hormone therapy alone had outcomes that were as good as those among women who received chemotherapy in addition to hormone therapy.
“Until now, we’ve been able to recommend treatment for women with these cancers at high and low risk of recurrence, but women at intermediate risk have been uncertain about the appropriate strategy to take,” said Jeffrey Abrams, M.D., associate director of NCI’s Cancer Therapy Evaluation Program. “These findings, showing no benefit from receiving chemotherapy plus hormone therapy for most patients in this intermediate-risk group, will go a long way to support oncologists and patients in decisions about the best course of treatment.”
The researchers found that the primary endpoint of the trial, invasive disease-free survival—the proportion of women who had not died or developed a recurrence or a second primary cancer—was very similar in both groups. Five years after treatment, the rate of invasive disease-free survival was 92.8 percent for those who had hormone therapy alone and 93.1 percent for those who also had chemotherapy. At nine years, the rate was 83.3 percent for those with hormone therapy alone and 84.3 percent for the group that had both therapies. None of these differences were considered statistically significant.
The rates of overall survival were also very similar in the two groups. At five years, the overall survival rate was 98.0 percent for those who received hormone therapy alone and 98.1 percent for those who received both therapies, and at nine years the respective overall survival rates were 93.9 percent and 93.8 percent.
The researchers also found that women with a score of 0–10 had very low recurrence rates with hormone therapy alone at nine years (3 percent). This confirms similar findings from earlier studies. In addition, they found that women with a score of 26–100 had a distant recurrence rate of 13 percent despite receiving both chemotherapy and hormone therapy. This finding indicates the need to develop more effective therapies for women at high risk of recurrence.
ECOG-ACRIN Cancer Research Group
ecog-acrin.org/news-and-info/press-releases/tailorx-trial-finds-most-women-with-early-breast-cancer-do-not-benefit-from-chemotherapy
A new drug to help young patients with genetic obesity
, /in E-News /by 3wmediaIn a new study researchers from the Institute for Experimental Pediatric Endocrinology of the Charité – Universitätsmedizin Berlin have successfully treated patients whose obesity is caused by a genetic defect. Aside from its beneficial effects on the patients, the researchers also provided insights into the fundamental signalling pathways regulating satiety of the new drug.
A mutation in the gene encoding the leptin receptor (LEPR) can cause extreme hunger starting with the first months of life. As a result, affected individuals develop extreme obesity during childhood. Increased exercise and reduced caloric intake are usually insufficient to stabilize body-weight. In many cases, obesity surgery fails to deliver any benefits, meaning that a drug-based treatment approach becomes increasingly important.
Two years ago, Dr. Peter Kühnen and the working group successfully demonstrated that treatment with a peptide, which activates the melanocortin 4 receptor (MC4R) could play a central role in the body’s energy metabolism and body weight regulation. Leptin, which is also known as the satiety (or starvation) hormone, normally binds to the LEPR, triggering a series of steps that leads to the production of melanocytestimulating hormone (MSH). The binding of MSH to its receptor, the melanocortin 4 receptor (MC4R) transduces the satiety signal to the body. However, if LEPR is defective, the signalling cascade is interrupted. The patient’s hunger remains unabated, placing her/him at greater risk of becoming obese. As part of this current study, researchers used a peptide that binds to the MC4R in the brain, and this activation triggers the normal satiety signal. Working in cooperation with the Clinical Research Unit at the Berlin Institute of Health (BIH), the researchers were able to record significant weight loss in patients with genetic defects affecting LEPR.
“We also wanted to determine why the used peptide was so effective and why, in contrast to other preparations with a similar mode of action, it did not produce any severe side effects,” explains Dr. Kühnen. “We were able to demonstrate that this treatment leads to the activation of a specific and important signalling pathway, whose significance had previously been underestimated.” Dr. Kühnen’s team is planning to conduct further research to determine whether other patients might benefit from this drug: “It is possible that other groups of patients with dysfunctions affecting the same signalling pathway might be suitable candidates for this treatment.”
Charité – Universitätsmedizin Berlin https://tinyurl.com/y7dyaqm4
How epigenetic regulation of the Hoxb gene cluster maintains normal blood-forming cells and inhibits leukemia
, /in E-News /by 3wmediaScientists have known for decades that the Hox family of transcription factors are key regulators in the formation of blood cells and the development of leukemia. Exactly how this large family of genes, which are distributed in four separate chromosomal clusters named A through D, is regulated has been less clear. Now, new research from the Stowers Institute for Medical Research reveals that a DNA regulatory element within the Hoxb cluster globally mediates signals to the majority of Hoxb genes to control their expression in blood-forming stem cells.
“It’s like we found a general control that simultaneously turns the lights on and off in many rooms, rather than having a single switch that controls each individual room,” says Stowers Investigator Linheng Li, PhD, who co-led the study along with Stowers Scientific Director and Investigator Robb Krumlauf, PhD. These findings also help explain why a particular form of leukemia resists treatment and points to potential new therapeutic avenues.
In mammals, the blood system contains a number of mature cell types — white blood cells, red blood cells, platelets — that arise from blood-forming, or hematopoietic, stem cells (HSCs). HSCs renew themselves and differentiate into other cells to replenish the body’s blood supply in a process called hematopoiesis. Hox genes, which are well known for their roles in establishing the body plan of developing organisms, are also important for HSCs to maintain their critical balancing act in the adult blood system, and have been implicated in the development of leukemia.
In an article Li, Krumlauf, and co-authors including first author Pengxu Qian, PhD, second author Bony De Kumar, PhD, and other collaborators provide new details as to how Hox genes are regulated in HSCs. They report that a single cis-regulatory element, DERARE, works over a long range to control the majority of Hoxb genes in HSCs in a coordinated manner. The researchers found that the loss of the DERARE decreased Hoxb expression and altered the types of blood cells arising from HSCs, whereas “turning on” DERARE allowed Hoxb cluster gene expression in progenitor cells and increased the progression of leukemia.
Genes can be regulated by non-coding DNA sequences termed cis-regulatory sequences. These sequences get input from multiple types of molecules, such as transcription factors, histone modifiers, or various morphogens. The DERARE, or distal element RARE (retinoic acid response element), is a cis-regulatory element that responds to signals from the vitamin A derivative retinoic acid and determines the fate of HSCs.
Using human leukemia cell lines and mouse models, the Stowers researchers and collaborators have identified a mechanism for how the retinoid-sensitive DERARE maintains normal hematopoiesis and prevents acute myeloid leukemia (AML) by regulating Hoxb cluster genes in a methylation-dependent manner.
Methylation is the process of adding methyl groups to the DNA molecule, which can change the activity of the DNA segment. The researchers demonstrated that DNA methyltransferases mediate DNA methylation on DERARE, leading to reduced Hoxb cluster expression. AML patients with mutations in the DNA methyltransferase DNMT3A exhibit reduced DERARE methylation, elevated Hoxb expression, and adverse outcomes.
“In two human AML cell lines carrying a DNMT3A mutation, we used an adaptation of genome editing technology called dCas9-DNMT3A to specifically increase the DNA methylation on DERARE. This targeted methylation technique was able to reduce Hoxb cluster expression and alleviate the progression of leukemia,” says Qian. “It is known that Hoxb cluster genes show a dramatic increase in expression in patients with DNMT3A-mutated AML. Our work provides mechanistic insights into the use of DNA methylation on the DERARE as a potential screening tool for therapeutic drugs that target DNMT3A-mutated AML, thus leading to the development of new drugs for treating AML, in which DNA methylation is abnormal.”
Stowers Institutehttps://tinyurl.com/yarf3xfd