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Shooting the Achilles Heel of Drug-Resistant Cancer

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Cancer cells that develop resistance to drugs, pay a price for this, by simultaneously developing a new vulnerability. If this acquired vulnerability can be identified, it may be exploited clinically. A team of cancer researchers, led by Rene Bernards of the Netherlands Cancer Institute and Oncode Institute, now exposed this acquired vulnerability in melanoma that has developed resistance to a targeted therapy with BRAF-inhibitors. The team then developed a new therapeutic strategy to selectively kill the drug-resistant cancer cells.

Do not fight resistance, but exploit it

One of the greatest obstacles in treating cancer is the rapid emergence of therapy resistance. However, when cancer cells develop drug resistance, they also acquire a new vulnerability, which is, in Darwinian terms, the fitness cost that comes with adapting to a new regime. If this newly acquired vulnerability can be exposed, it may be exploited clinically to keep the cancer at bay for a longer period, according to cancer researcher Rene Bernards.

Professor Bernards: ‘Drug resistance seems inevitable because tumours are constantly adapting. For over 40 years, we have been devising ways to prevent drug resistance in cancer. Now I think: let’s just accept that this is the way it is, and go and see if we can find the new vulnerability associated with resistance. Then we can exploit this sensitivity clinically and keep the cancer under control for a longer time.’

Melanoma

Bernards and his team were able to expose this new vulnerability in melanoma that has developed resistance to treatment with a BRAF inhibitor: a targeted therapy that blocks a signalling pathway in the cancer cell through which it gets the message to keep on dividing. This is due to a mutation in the BRAF gene, which plays an important role in cell division in healthy cells. More than half of all melanoma patients have a mutation in this BRAF gene. For these people, the BRAF-inhibitor does its job and tumour growth stops. But within a few months the tumour cell adapts the original signalling pathway becomes active again, and even hyperactive, so that all lights are green to start growing again.

Reactive oxygen species cause DNA damage

The key question is: what price does melanoma pay for resistance? In the lab, the researchers made melanoma cells resistant to the BRAF inhibitor and saw that the hyperactive resistant melanoma cells produced large amounts of reactive oxygen species. Cancer cells that were still sensitive to the drug did not do this.

Reactive oxygen species are — both in healthy cells and in cancer cells — a double-edged sword. They play an important role in transmitting signals in the cell, but if their concentration becomes too high, they cause DNA damage and the cell may stop dividing. Also in the Bernards experiment, the abundance of free radicals caused the resistant melanoma cells to stop dividing. However: they did not die.

Last push towards cell death

Bernards: ‘Then we thought: suppose we can give those hyperactive resistant tumour cells the last push towards cell death, by allowing them to produce even more free radicals.’ In the lab, this worked perfectly by exposing the cells to a substance that stimulates the production of free oxygen radicals. Only the resistant tumour cells died; tumour cells that were still sensitive to the original drug remained alive.

Tumours shrink

But does this also work in a living organism with melanoma? Bernards tested this on mice with an existing drug, vorinostat, which is known to stimulate the production of free oxygen radicals. Vorinostat has been used in the clinic for 15 years, including for a rare form of lymphoma, and is not very harmful to the patient. In mouse models, the researchers did indeed see tumours shrink under the influence of vorinostat.

Quickly onto a clinical trial

This gave hope, and because it was an approved and safe medicine, Bernards could then, together with physician Jan Schellens and hospital pharmacist Jos Beijnen, quickly start a clinical proof-of-concept trial among a very small number of patients of the Netherlands Cancer Institute. The concept also appeared to work in patients.

One-two punch strategy

This laid the foundation for a new therapeutic strategy. Step one: treat patients with BRAF-mutated melanoma, as usual, with signal pathway inhibitors. Step two: when the tumour has become resistant, stop giving those inhibitors and immediately treat the patients with vorinostat to kill the resistant cancer cells. For boxing enthusiasts: a ‘one-two punch’ approach. A hit from the left, immediately followed by one from the right.

“It is not a combination drug,” emphasizes Bernards, who has made a name for himself with smart combinations of drugs. ‘It is very important that you first stop the signalling pathway inhibitors because they suppress the free radicals and thus eliminate the effects of vorinostat.’

Getting new cancer drugs quickly and cheaply to the clinic

Bernards is happy with his scientific research, which resulted in a well-founded new strategy to treat melanoma that has become resistant. But he is at least as happy with the speed with which a lab study resulted in a clinical trial. ‘It is unique that a clinical trial has already been part of a fundamental scientific publication. This is how we, increasingly, want to do it.’

And moreover, the costing details are favourable. Vorinostat is a notoriously expensive drug, but hospital pharmacist, Beijnen, can make it himself in the pharmacy of Netherlands Cancer Institute. This is permitted for a clinical trial, and there is also no longer a patent on the American medicine. Bernards: ‘That is why this research fits so well with the new Oncode Institute, whose mission it is to bring new treatments to the patient quickly and cheaply.’

Follow-up step 1: nip resistance in the bud

Two follow-up studies are now planned. The first is a clinical follow-up study, under the umbrella of Oncode Institute. Bernards: ‘In our clinical proof-of-concept study, we gave the patients BRAF inhibitors for one year, until the cancer had become resistant. We then exterminated the resistant cells in one month with vorinostat. Now that we know that this principle works, we want to go a step further: we are going to check the patients’ blood every month for mutations in the tumor DNA. As soon as we see a trace of resistance, we briefly treat with vorinostat to nip the resistance in the bud. Then, we again transfer to the BRAF inhibitors, until we see resistance emerge again. With such a pulse-treatment, we think we can keep the cancer under control longer. ‘

Follow-up step 2: find the Achilles heel of other resistant cancers

In addition, Bernards will soon start a major study in which he wants to induce and exploit senescence in cancers other than melanoma. He has just been informed that the European Research Council will invest 2.5 million Euros in this, in the form of an ERC Advanced Grant.

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Children Carry Evidence Of Toxins From Home Flooring And Furniture

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Children living in homes with all vinyl flooring or flame-retardant chemicals in the sofa have significantly higher concentrations of potentially harmful semi-volatile organic compounds (SVOCs) in their blood or urine than children from homes where these materials are not present, according to a new Duke University-led study.

The researchers presented their findings Sunday, Feb. 17 at the annual meeting of the American Association for the Advancement of Science in Washington, D.C.

They found that children living in homes where the sofa in the main living area contained flame-retardant polybrominated diphenyl ethers (PBDEs) in its foam had a six-fold higher concentration of PBDEs in their blood serum.

Exposure to PBDEs has been linked in laboratory tests to neurodevelopmental delays, obesity, endocrine and thyroid disruption, cancer and other diseases.

Children from homes that had vinyl flooring in all areas were found to have concentrations of benzyl butyl phthalate metabolite in their urine that were 15 times higher than those in children living with no vinyl flooring.

Benzyl butyl phthalate has been linked to respiratory disorders, skin irritations, multiple myeolma and reproductive disorders.

“SVOCs are widely used in electronics, furniture and building materials and can be detected in nearly all indoor environments,” said Heather Stapleton, an environmental chemist at Duke’s Nicholas School of the Environment, who led the research.

“Human exposure to them is widespread, particularly for young children who spend most of their time indoors and have greater exposure to chemicals found in household dust.”

“Nonetheless, there has been little research on the relative contribution of specific products and materials to children’s overall exposure to SVOCs,” she noted.

To address that gap, in 2014 Stapleton and colleagues from Duke, the Centers for Disease Control & Prevention, and Boston University began a three-year study of in-home exposures to SVOCs among 203 children from 190 families.

“Our primary goal was to investigate links between specific products and children’s exposures, and to determine how the exposure happened — was it through breathing, skin contact or inadvertent dust inhalation,” Stapleton said.

To that end, the team analyzed samples of indoor air, indoor dust and foam collected from furniture in each of the children’s homes, along with a handwipe sample, urine and blood from each child.

“We quantified 44 biomarkers of exposure to phthalates, organophosphate esters, brominated flame retardants, parabens, phenols, antibacterial agents and perfluoroalkyl and polyfluoroalkyl substances (PFAS),” Stapleton said.

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Your Home Is A Hidden Source Of Air Pollution

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Cooking, cleaning and other routine household activities generate significant levels of volatile and particulate chemicals inside the average home, leading to indoor air quality levels on par with a polluted major city, University of Colorado Boulder researchers have found.

What’s more, airborne chemicals that originate inside a house don’t stay there: Volatile organic compounds (VOCs) from products such as shampoo, perfume and cleaning solutions eventually escape outside and contribute to ozone and fine particle formation, making up an even greater source of global atmospheric air pollution than cars and trucks do.

The previously underexplored relationship between households and air quality drew focus today at the 2019 AAAS Annual Meeting in Washington, D.C., where researchers from CU Boulder’s Cooperative Institute for Research in Environmental Sciences (CIRES) and the university’s Department of Mechanical Engineering presented their recent findings during a panel discussion.

“Homes have never been considered an important source of outdoor air pollution and the moment is right to start exploring that,” said Marina Vance, an assistant professor of mechanical engineering at CU Boulder.

“We wanted to know: How do basic activities like cooking and cleaning change the chemistry of a house?”

In 2018, Vance co-led the collaborative HOMEChem field campaign, which used advanced sensors and cameras to monitor the indoor air quality of a 1,200-square-foot manufactured home on the University of Texas Austin campus. Over the course of a month, Vance and her colleagues conducted a variety of daily household activities, including cooking a full Thanksgiving dinner in the middle of the Texas summer.

While the HOMEChem experiment’s results are still pending, Vance said that it’s apparent that homes need to be well ventilated while cooking and cleaning, because even basic tasks like boiling water over a stovetop flame can contribute to high levels of gaseous air pollutants and suspended particulates, with negative health impacts.

To her team’s surprise, the measured indoor concentrations were high enough that that their sensitive instruments needed to be recalibrated almost immediately.

“Even the simple act of making toast raised particle levels far higher than expected,” Vance said.

“We had to go adjust many of the instruments.”

Indoor and outdoor experts are collaborating to paint a more complete picture of air quality, said Joost de Gouw, a CIRES Visiting Professor. Last year, de Gouw and his colleagues published results in the journal Science showing that regulations on automobiles had pushed transportation-derived emissions down in recent decades while the relative importance of household chemical pollutants had only gone up.

“Many traditional sources like fossil fuel-burning vehicles have become much cleaner than they used to be,” said de Gouw.

“Ozone and fine particulates are monitored by the EPA, but data for airborne toxins like formaldehyde and benzene and compounds like alcohols and ketones that originate from the home are very sparse.”

While de Gouw says that it is too early on in the research to make recommendations on policy or consumer behavior, he said that it’s encouraging that the scientific community is now thinking about the “esosphere,” derived from the Greek word ‘eso,’ which translates to ‘inner.’

“There was originally skepticism about whether or not these products actually contributed to air pollution in a meaningful way, but no longer,” de Gouw said.

“Moving forward, we need to re-focus research efforts on these sources and give them the same attention we have given to fossil fuels. The picture that we have in our heads about the atmosphere should now include a house.”

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Diet Drinks May Be Associated With Strokes Among Post-Menopausal Women

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Among post-menopausal women, drinking multiple diet drinks daily was associated with an increase in the risk of having a stroke caused by a blocked artery, especially small arteries, according to research published in Stroke, a journal of the American Heart Association.

This is one of the first studies to look at the association between drinking artificially sweetened beverages and the risk of specific types of stroke in a large, racially diverse group of post-menopausal women. While this study identifies an association between diet drinks and stroke, it does not prove cause and effect because it was an observational study based on self-reported information about diet drink consumption.

Compared with women who consumed diet drinks less than once a week or not at all, women who consumed two or more artificially sweetened beverages per day were:

  • 23 percent more likely to have a stroke;
  • 31 percent more likely to have a clot-caused (ischemic) stroke;
  • 29 percent more likely to develop heart disease (fatal or non-fatal heart attack); and
  • 16 percent more likely to die from any cause.

Researchers found risks were higher for certain women. Heavy intake of diet drinks, defined as two or more times daily, more than doubled stroke risk in:

  • women without previous heart disease or diabetes, who were 2.44 times as likely to have a common type of stroke caused by blockage of one of the very small arteries within the brain;
  • obese women without previous heart disease or diabetes, who were 2.03 times as likely to have a clot-caused stroke; and
  • African-American women without previous heart disease or diabetes, who were 3.93 times as likely to have a clot-caused stroke.

“Many well-meaning people, especially those who are overweight or obese, drink low-calorie sweetened drinks to cut calories in their diet. Our research and other observational studies have shown that artificially sweetened beverages may not be harmless and high consumption is associated with a higher risk of stroke and heart disease,” said Yasmin Mossavar-Rahmani, Ph.D., lead author of the study and associate professor of clinical epidemiology and population health at the Albert Einstein College of Medicine in the Bronx, New York.

Researchers analyzed data on 81,714 postmenopausal women (age 50-79 years at the start) participating in the Women’s Health Initiative study that tracked health outcomes for an average of 11.9 years after they enrolled between 1993 and 1998. At their three-year evaluation, the women reported how often in the previous three months they had consumed diet drinks such as low calorie, artificially sweetened colas, sodas and fruit drinks. The data collected did not include information about the specific artificial sweetener the drinks contained.

The results were obtained after adjusting for various stroke risk factors such as age, high blood pressure, and smoking. These results in postmenopausal women may not be generalizable to men or younger women. The study is also limited by having only the women’s self-report of diet drink intake.

“We don’t know specifically what types of artificially sweetened beverages they were consuming, so we don’t know which artificial sweeteners may be harmful and which may be harmless,” Mossavar-Rahmani said.

The American Heart Association recently published a science advisory that found there was inadequate scientific research to conclude that low-calorie sweetened beverages do – or do not – alter risk factors for heart disease and stroke in young children, teens or adults. The Association recognizes diet drinks may help replace high calorie, sugary beverages, but recommends water (plain, carbonated and unsweetened flavored) as the best choice for a no calorie drink.

“Unfortunately, current research simply does not provide enough evidence to distinguish between the effects of different low-calorie sweeteners on heart and brain health. This study adds to the evidence that limiting use of diet beverages is the most prudent thing to do for your health,” said Rachel K. Johnson, Ph.D., R.D., professor of nutrition emeritus, University of Vermont and the chair of the writing group for the American Heart Association’s science advisory, Low-Calorie Sweetened Beverages and Cardiometabolic Health.

“The American Heart Association suggests water as the best choice for a no-calorie beverage. However, for some adults, diet drinks with low calorie sweeteners may be helpful as they transition to adopting water as their primary drink. Since long-term clinical trial data are not available on the effects of low-calorie sweetened drinks and cardiovascular health, given their lack of nutritional value, it may be prudent to limit their prolonged use” said Johnson.

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