Researchers discover key to drug resistance in common breast cancer treatment

Three-quarters of all breast cancer tumours are driven by the hormone oestrogen. These tumours are frequently treated with drugs to suppress oestrogen receptor activity, but unfortunately, at least half of patients do not respond to these treatments, leaving them with drug-resistant tumours and few options.

Now, scientists from the Florida campus of The Scripps Research Institute (TSRI), the University of California (UC), San Diego and the University of Illinois have found that two immune system molecules may be key to the development of drug resistance in oestrogen-driven breast cancers. The researchers believe this finding may open the door to novel therapeutic approaches and influence treatment decisions for the tens of thousands of patients who suffer from oestrogen-driven breast cancers.

These molecules, which are cytokines called interleukin 1 beta (IL1) and tumour necrosis factor alpha (TNF), had previously been linked to the spread of drug-resistant cancer, but scientists were unsure of the exact mechanisms that led these molecules to drive drug resistance.

The study published in the journal Molecular Cell, reveals that IL1 and TNF turn on pathways that modify the actual shape of the oestrogen receptor. This phenomenon appears to drive resistance to the common anti-cancer drug tamoxifen.

“Cytokines change the shape of the oestrogen receptor, and that change overrides the inhibitory effects of tamoxifen and leads to drug resistance,” said TSRI Associate Professor Kendall Nettles, who led the new study alongside senior author Christopher K. Glass and study first author Joshua D. Stender of UC San Diego. “These findings dramatically alter our understanding of the biological actions of pro-inflammatory cytokines in breast cancer cells.”

Using a combination of genomic, cellular, biochemical and structural approaches, the researchers found that the way these cytokines alter the oestrogen receptor are sufficient to induce growth of breast cancer cells in the absence of oestrogen, precisely what happens when breast cancer is initially treated with an endocrine therapy like tamoxifen. Scientists found that in addition to reversing tamoxifen suppression of growth, cytokine activation of the oestrogen receptor also enhanced the invasive properties of a specific line of human breast cancer cells known as MCF-7, the most studied human breast cancer cell in in the world.

Using x-ray crystallography, Prof. Nettles and his colleagues developed an atomic snapshot of the oestrogen receptor to show how these shape changes occur and how the process might be blocked.

Nettles pointed out that both inflammation and immune cells are known causes of resistance, but if that inflammation can be blocked, resistance can be reduced or eliminated.

“These tumours can reprogram the immune cells to their advantage so that the cells become tumour supportive,” Prof. Nettles said. “We think we can produce hormone therapies that can, in essence, re-reprogram the immune system or prevent it from altering the receptor in the first place, which is an obvious strategy for blocking these adverse effects. Importantly, our atomic snapshot of the receptor showed that the same mechanism can explain how Her2Neu or other growth promoting factors, as well as certain invasion and motility signals also cause resistance to anti-hormone therapies.”

  • doi: 10.1016/j.molcel.2017.02.008

New understanding of blood-brain barrier

US National Institutes of Health researchers studying zebrafish have determined that a population of cells that protect the brain against diseases and harmful substances are not immune cells, as had previously been thought, but instead likely arise from the lining of the circulatory system.

This basic science finding may have implications for understanding age-related decline in brain functioning and how HIV infects brain cells.

The study, appears online in eLife, was conducted by researchers at NIH’s Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and National Human Genome Research Institute and the Japanese National Institute of Genetics.

The blood-brain barrier is the layer of cells that line the blood vessels of the brain. The inner cell layer that lines vessels, known as the endothelium, is present in all the blood vessels of the body. Within the blood vessels of the brain, endothelial cells and other adjacent cells form a tight barrier that helps to prevent toxins and microbes from entering the brain. Although their function is not completely understood, a special population of cells covering the blood vessels on the brain’s surface is thought to contribute to the organ’s protection. The cells act as sentries, engulfing toxins, cellular wastes and microbes and then encasing them in spherelike structures called vesicles. These sentry cells are called fluorescent granular perithelial cells (FGPs) because the vesicles they contain give off a yellow glow in the presence of light.

In the current study, the researchers showed that FGPs are present on the surface of the zebrafish brain and that these blood vessel-associated FGPs do not arisefrom the immune system, as had been previously thought, but from endothelial cells themselves.

FGPs are thought to be important in a variety of human brain disorders and conditions. These cells appear to be a major entry point for HIV infection of the brain. Age-related decline in cognitive function is associated with a decline in the scavenging function of FGPs. “Learning more about how FGPs function may lead to a greater understanding of dementia and other conditions,” said the study’s senior author, Brant Weinstein, Ph.D., of NICHD’s Section on Vertebrate Organogenesis.

The Weinstein lab studies zebrafish to understand how the blood and lymphatic systems develop. Because the young fish are transparent, it is possible to see the developing circulatory system while observing the fish under a light microscope. As part of this effort, Dr Weinstein and his colleagues inserted a gene for a protein that turns green into the cells that line the endothelium of selected embryonic veins and in the lymphatic system -- the network of vessels through which immune cells travel in the body. In addition to seeing green lymphatic cells in the zebrafish embryos, the researchers noticed that green cells also covered the surface of the tiny fish’s brains.

Upon closer inspection, the researchers tentatively identified these cells as FGPs. Because they turned green, it was apparent that they arose from endothelial cells. Until the current study, FGPs were thought to be macrophages, a type of immune cell. The researchers conducted additional experiments to confirm the origins of the FGPs, including analysing what proteins were being made by their DNA. These proteins most closely resembled those made by endothelial cells in the lymphatic system, not the proteins made by macrophages or other immune cells. In another series of experiments, they inserted a green fluorescent protein into the tissues that give rise to blood and lymph vessels in embryonic zebrafish. Using time lapse photography, the researchers captured images of FGPs arising from the vessels’ endothelium. When zebrafish with the green fluorescing endothelial gene matured, the researchers observed green FGPs on the surface of the fish’s brains -- confirming that these cells arose from endothelial tissue.

The researchers hope to conduct further studies of how FGPs interact with blood vessels and the blood-brain barrier.


Diabetes damages small blood vessels around heart, ups risk of heart attack

Diabetics have a significantly higher risk of suffering a heart attack. A research team at the Technical University of Munich (TUM) has now identified one of the causes: Diabetes is associated with the loss of small blood vessels around the heart. This in turn affects the entire cardiac muscle. A genetic therapy that promotes the growth of blood vessels may offer a remedy.

The coronary vessels can be compared to a road network. Veins and arteries form the main transportation routes, with countless small and minuscule connecting roads and access pathways branching off from them. If one of these little pathways is blocked, it has very little impact on the overall traffic flow. But if enough of the offramps are closed, the traffic on the main highway becomes very dense. In a worstcase scenario, the entire system comes to a standstill: a heart attack.

A team headed by TUM has found out that diabetes can lead to these very conditions. The scientists working with Dr Rabea Hinkel and Prof. Christian Kupatt, cardiologists at TUM’s Klinikum rechts der Isar, have reported their results in the Journal of the American College of Cardiology.

In their research they compared blood vessels of patients with and without diabetes undergoing heart transplants. The conclusion: The samples from diabetics showed significantly reduced numbers of small blood vessels around the heart.

In the laboratory the team was able to show that elevated blood sugar levels are associated with a loss of cells known as pericytes. “These cells normally form a layer wrapped around the small blood vessels,” explains Hinkel. “We believe that this layer has a stabilizing function. When it is damaged, the entire blood vessel becomes unstable and ultimately breaks up.”

Animal experiments confirmed the assumption of a steady decrease in capillary density around the heart when diabetes is left untreated. “Diabetes often remains undetected in patients for years or even decades. Over that long period, massive damage can occur,” says Hinkel. The loss of capillaries is not irreversible, however. In their study, Hinkel and Kupatt applied a genetic therapy to stimulate heart cells to increase production of the molecule thymosin beta 4, a protein whose effects include stimulating the growth of pericytes. In this way, the team at TUM was able to induce the growth of lasting and functional capillary networks.

“It will be a while before this kind of therapy can be used in humans,” says Christian Kupatt. “But we were able to show for the first time in a transgenic large animal model, which closely models human type I diabetes mellitus, how diabetes damages the heart. That opens up new perspectives for treating patients. It also further reinforces our awareness of how important it is to diagnose diabetes early.”

  • doi: 10.1016/j.jacc.2016.10.058

 


Link between herpes virus and brain cancer disputed with new study

In a rigorous study of tumour tissue collected from 125 patients with aggressive brain cancers, researchers at Johns Hopkins say they have found no evidence of cytomegalovirus (CMV) infection and conclude that a link between the two diseases, as claimed by earlier reports, likely does not exist.

As early as 2002, the Johns Hopkins team says, several studies reported that tumour cells isolated within glioblastomas and other gliomas were infected with CMV, a herpes virus that infects more than half of all adults by age 40 and is related to viruses that cause chickenpox and mononucleosis.

The Johns Hopkins team cautioned that studies to confirm their finding are needed to absolutely rule out any role for the commonCMV in glioblastoma and other cancers that arise in neurological support cells called glial cells. But they say their study substantially weakens the likelihood of that role.

“We have found no evidence of CMV in these tissues, and if there is no virus, targeting that virus to affect cancer using antiviral drugs or tailored vaccines doesn’t make biological sense,” says Angelo M. De Marzo, M.D., Ph.D., professor of pathology, oncology and urology at the Johns Hopkins Kimmel Cancer Center.

A report on the research was published December 29, 2016 in Clinical Cancer Research.

Because other viruses are associated with some cancers, notably HPV, which causes most cervical and some head and neck cancers; and Epstein-Barr virus, which causes some lymphomas, those earlier findings generated excitement about the potential for antiviral therapies to improve the usually poor outlook for people with gliomas.

However, explains Matthias Holdhoff, M.D., Ph.D., associate professor of oncology and neurosurgery at the Johns Hopkins Kimmel Cancer Center, other laboratories found no evidence of the virus in these types of tumours. “Significant resources have already gone into this field of study,” he says, “making it very important to definitively answer the question of whether there’s an association between CMV and gliomas or not.”


Insomnia associated with increased risk of heart attack and stroke

Insomnia is associated with increased risk of heart attack and stroke, according to research published March 31, 2017 in the European Journal of Preventive Cardiology.

“Sleep is important for biological recovery and takes around a third of our lifetime, but in modern society more and more people complain of insomnia,” said first author Qiao He, a Master’s degree student at China Medical University, Shenyang, China. “For example, it is reported that approximately one-third of the general population in Germany has suffered from insomnia symptoms.”

“Researchers have found associations between insomnia and poor health outcomes,” continued He. “But the links between insomnia and heart disease or stroke have been inconsistent.”

The current meta-analysis assessed the association between insomnia symptoms and incidence or death from cardiovascular disease (acute myocardial infarction, coronary heart disease, heart failure), stroke, or a combination of events. Insomnia symptoms included difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening, and non-restorative sleep.

The authors analysed 15 prospective cohort studies with a total of 160,867 participants. During a median follow-up of three to 29.6 years, there were 11,702 adverse events.

There were significant associations between difficulty initiating sleep, difficulty maintaining sleep, and non-restorative sleep and the risk of heart disease and stroke, with increased relative risks of 1.27, 1.11, and 1.18, respectively, compared to those not experiencing these insomnia symptoms. There was no association between early-morning awakening and adverse events.

He said: “We found that difficulty initiating sleep, difficulty maintaining sleep, or non-restorative sleep were associated with 27%, 11%, and 18% higher risks of cardiovascular and stroke events, respectively.

“The underlying mechanisms for these links are not completely understood,” continued He. “Previous studies have shown that insomnia may change metabolism and endocrine function, increase sympathetic activation, raise blood pressure, and elevate levels of proinflammatory and inflammatory cytokines – all of which are risk factors for cardiovascular disease and stroke.”

Women with insomnia symptoms had a slightly higher risk of cardiovascular and stroke events than men, especially for nonrestorative sleep, but the difference between sexes did not reach statistical significance.

He said: “We cannot conclude that insomnia is more dangerous for women, given the limitations of meta-analyses and the lack of a statistically significant difference between sexes. However, we do know that women are more prone to insomnia because of differences in genetics, sex hormones, stress, and reaction to stress. It may therefore be prudent to pay more attention to women’s sleep health.”

He concluded: “Sleep disorders are common in the general population and sleep health should be included in clinical risk assessment. Health education is needed to increase public awareness of insomnia symptoms and the potential risks, so that people with sleep problems are encouraged to seek help.”

  • doi: 10.1177/2047487317702043

Monoclonal antibody cures Marburg infection in monkeys

Scientists funded by the US National Institutes of Health have found that an experimental treatment cured 100% of guinea pigs and rhesus monkeys in late stages of infection with lethal levels of Marburg and Ravn viruses, relatives of the Ebola virus. Although the Marburg and Ravn viruses are less familiar than Ebola virus, both can resemble Ebola in symptoms and outcomes in people, and both lack preventive and therapeutic countermeasures.

The study involved giving the animals a therapeutic candidate, MR191-N, which is a monoclonal antibody derived from a person who survived Marburg disease. Monoclonal antibodies are immune system fighters designed to bind to a specific part of an invading virus or bacterium to treat disease. The authors report that two doses of MR191-N were able to confer protection of up to 100% when treatment was started up to 5 days post infection. Prior studies of different experimental Marburg treatments involved daily dosing for 7 and 14 days, respectively, with treatment beginning closer to the time of infection.

The study was led by scientists at the University of Texas Medical Branch Galveston National Laboratory and Mapp Biopharmaceutical, Inc., and included collaborators from Vanderbilt University Medical Center, the University of Natural Resources and Life Sciences in Austria, and The Scripps Research Institute. The NIH’s National Institute of Allergy and Infectious Diseases (NIAID) provided project funding.

The researchers are now working with NIAID’s preclinical services group to perform the additional safety testing necessary to advance the monoclonal antibody treatment to initial human clinical studies. Public health workers learned during the 2014-15 Ebola outbreak in West Africa that lack of available treatment options kept diseased and at-risk people away from treatment centres, making disease tracking and outbreak containment more difficult. They fear the same situation would develop in a large-scale Marburg outbreak.

  • doi: 10.1126/scitranslmed.aai8711

New ‘gene silencer’ drug reduces cholesterol by over 50%

The first in a new class of gene-silencing drugs, known as inclisiran, has been shown to halve cholesterol levels in patients at risk of cardiovascular disease.

The findings come from the largest trial yet to test the safety and effectiveness of this kind of therapy. The technique, known as RNA interference (RNAi) therapy, essentially ‘switches off’ one of the genes responsible for elevated cholesterol.

Researchers from Imperial College London and their colleagues, who conducted the trial, say the twice-a-year treatment could be safely given with or without statins, depending on individual patient needs. Eventually, inclisiran could help to reduce the risk of heart attacks and stroke related to high cholesterol.

“These initial results are hugely exciting for patients and clinicians,” said Professor Kausik Ray, lead author of the study from the School of Public Health at Imperial.

“We appear to have found a versatile, easy-to-take, safe, treatment that provides sustained lowering of cholesterol levels and is therefore likely to reduce the risk of cardiovascular disease, heart attacks, and stroke. These reductions are over and above what can be already be achieved with statins alone or statins plus ezetemibe, another class of cholesterol-lowering drug.

Elevated levels of low-density lipoprotein (LDL) cholesterol can lead to cardiovascular disease and blood vessel blockage, leading to an increased risk heart attacks and stroke in patients.

Statins are currently the standard treatment for high cholesterol, combined with exercise and healthy diet, as they reduce levels in the blood and therefore help to prevent heart attacks and stroke.

However, some patients are unable to tolerate the highest doses and they need.

Now, this new phase 2 clinical trial has confirmed the effectiveness of injecting inclisiran for reducing cholesterol that can be taken alone or potentially combined with statins for maximum effect.

In the study, researchers gave 497 patients with high cholesterol and at high risk of cardiovascular disease either inclisiran at varying doses, or placebo. Seventy-three per cent of these patients were already taking statins, and 31% were taking ezetimibe. Participants, who were recruited from Canada, USA, Germany, Netherlands, and the UK, were excluded if they were taking monoclonal antibodies for cholesterol lowering.

Patients were given different doses of inclisiran or placebo via subcutaneous injection, either via a single dose, or via a dose on day one and another at three months. They were followed up regularly for a subsequent eight months and tested for blood cholesterol and side effects.

The researchers found that just one month after receiving a single treatment of inclisiran, participants’ LDL cholesterol levels had reduced by up to 51%.

In those on a single dose of 300 mg, cholesterol levels were reduced by 42% at six months. In the matched placebo group, cholesterol levels had increased by two per cent within that time frame.

In those on two doses of 300 mg, cholesterol levels were reduced by up to 53% at six months. Moreover, cholesterol levels had gone down for all patients in this group, and 48% of them had achieved cholesterol levels (below 50 mL/dL).

In all patients, cholesterol levels stayed lower for at least eight months. No extra side effects were seen in the study group compared to the placebo group.

The study will follow up patients for a further four months (one year total follow up). The results from this trial, known as ORION-1, are published in the New England Journal of Medicine.

The authors say the results show the drug acts quickly to reduce cholesterol levels by as early as two weeks post-injection, while also giving a prolonged effect when given in two doses over a year. Therefore, the next step is to conduct an extended study, using more patients and for a longer period of time, to determine whether these reductions in cholesterol translate into a reduction in heart attacks and strokes.

Aside from its effectiveness, the authors point out that because inclisiran acts on a different biological pathway to statins, the two drugs would likely be combined for the best results.

  • doi: 10.1056/NEJMoa1615758

 


Newer medications cure HCV infections

 

A new analysis reveals a dramatic transformation in the care of patients infected with hepatitis C virus (HCV) as more effective and tolerable medications have become available.

In an analysis of all HCV antiviral treatment regimens (N=107,079) initiated from 1999 through 2015 in the US Veterans Affairs national healthcare system, cure rates increased steadily from 19.2% in 1999 to 36.0% in 2010 before a remarkable increase to 90.5% in 2015. The number of patients achieving sustained virologic response was 1313 in 2010, the last year of the interferon era and increased 5.6-fold to 7377 in 2014 and 21-fold to 28,084 in 2015.

“The introduction of effective direct antiviral agents together with the allocation of appropriate funds and resources allowed the VA healthcare system to treat and cure hepatitis C in unprecedented numbers. In fact, out of approximately 57,500 patients cured of hepatitis C in the VA since 1999, approximately half were cured in a single year in 2015,” said Dr George Ioannou, senior author of the Alimentary Pharmacology and Therapeutics analysis.

“The question is whether we are delivering these medications to the patients who need them and what obstacles there are to treating and curing the majority of hepatitis C infected patients.”

  • doi: 10.1111/apt.14021

 

Date of upload: 20th May 2017

                                  
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