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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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Paternal Transmission Of Epigenetic Memory Via Sperm

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Studies of human populations and animal models suggest that a father’s experiences such as diet or environmental stress can influence the health and development of his descendants. How these effects are transmitted across generations, however, remains mysterious.

Susan Strome’s lab at UC Santa Cruz has been making steady progress in unraveling the mechanisms behind this phenomenon, using a tiny roundworm called Caenorhabditis elegans to show how marks on chromosomes that affect gene expression, called “epigenetic” marks, can be transmitted from parents to offspring. Her team’s most recent paper, published October 17 in Nature Communications, focuses on transmission of epigenetic marks by C. elegans sperm.

In addition to documenting the transmission of epigenetic memory by sperm, the new study shows that the epigenetic information delivered by sperm to the embryo is both necessary and sufficient to guide proper development of germ cells in the offspring (germ cells give rise to eggs and sperm).

“We decided to look at C. elegans because it is such a good model for asking epigenetic questions using powerful genetic approaches,” said Strome, a distinguished professor of molecular, cell, and developmental biology.

Epigenetic changes do not alter the DNA sequences of genes, but instead involve chemical modifications to either the DNA itself or the histone proteins with which DNA is packaged in the chromosomes. These modifications influence gene expression, turning genes on or off in different cells and at different stages of development. The idea that epigenetic modifications can cause changes in gene expression that are transmitted from one generation to the next, known as “transgenerational epigenetic inheritance,” is now the focus of intense scientific investigation.

For many years, it was thought that sperm do not retain any histone packaging and therefore could not transmit histone-based epigenetic information to offspring. Recent studies, however, have shown that about 10 percent of histone packaging is retained in both human and mouse sperm.

“Furthermore, where the chromosomes retain histone packaging of DNA is in developmentally important regions, so those findings raised awareness of the possibility that sperm may transmit important epigenetic information to embryos,” Strome said.

When her lab looked at C. elegans sperm, they found the sperm genome fully retains histone packaging. Other researchers had found the same is true for another commonly studied organism, the zebrafish.

“Like zebrafish, worms represent an extreme form of histone retention by sperm, which makes them a great system to see if this packaging really matters,” Strome said.

Her lab focused on a particular epigenetic mark (designated H3K27me3) that has been well established as a mark of repressed gene expression in a wide range of organisms. The researchers found that removing this mark from sperm chromosomes causes the majority of the offspring to be sterile. Having established that the mark is important, they wanted to see if it is sufficient to guide normal germline development.

The researchers addressed this by analyzing a mutant worm in which the chromosomes from sperm and egg are separated in the first cell division after fertilization, so that one cell of the embryo inherits only sperm chromosomes and the other cell inherits only egg chromosomes (normally, each cell of an embryo inherits chromosomes from both egg and sperm). This unusual chromosome segregation pattern allowed the researchers to generate worms whose germ line inherited only sperm chromosomes and therefore only sperm epigenetic marks. Those worms turned out to be fertile and to have normal gene expression patterns.

“These findings show that the DNA packaging in sperm is important, because offspring that did not inherit normal sperm epigenetic marks were sterile, and it is sufficient for normal germline development,” Strome said.

While the study shows that epigenetic information transmitted by sperm is important for normal development, it does not directly address how the life experience of a father can affect the health of his descendants. Strome’s lab is investigating this question with experiments in which worms are treated with alcohol or starved before reproducing.

“The goal is to analyze how the chromatin packaging changes in the parent,” she said.

“Whatever gets passed on to the offspring has to go through the germ cells. We want to know which cells experience the environmental factors, how they transmit that information to the germ cells, what changes in the germ cells, and how that impacts the offspring.”

By demonstrating the importance of epigenetic information carried by sperm, the current study establishes that if the environment experienced by the father changes the epigenetics of sperm chromosomes, it could affect the offspring.

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Father’s Nicotine Use Can Cause Cognitive Problems In Children And Grandchildren

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A father’s exposure to nicotine may cause cognitive deficits in his children and even grandchildren, according to a study in mice publishing on October 16 in the open-access journal PLOS Biology by Pradeep Bhide of Florida State University in Tallahassee and colleagues. The effect, which was not caused by direct secondhand exposure, may be due to epigenetic changes in key genes in the father’s sperm.

Exposure of mothers to nicotine and other components of cigarette smoke is recognized as a significant risk factor for behavioral disorders, including attention deficit hyperactivity disorder, (or ADHD) in multiple generations of descendants. Whether the same applies to fathers has been less clear, in part because in human studies it has been difficult to separate genetic factors (such as a genetic predisposition to ADHD) from environmental factors, such as direct exposure to cigarette smoke.

To overcome this difficulty, Deirdre McCarthy, Pradeep Bhide and colleagues exposed male mice to low-dose nicotine in their drinking water during the stage of life in which the mice produce sperm. They then bred these mice with females that had never been exposed to nicotine. While the fathers were behaviorally normal, both sexes of offspring displayed hyperactivity, attention deficit, and cognitive inflexibility. When female (but not male) mice from this generation were bred with nicotine-naïve mates, male offspring displayed fewer, but still significant, deficits in cognitive flexibility. Analysis of spermatozoa from the original nicotine-exposed males indicated that promoter regions of multiple genes had been epigenetically modified, including the dopamine D2 gene, critical for brain development and learning, suggesting that these modifications likely contributed to the cognitive deficits in the descendants.

Nicotine and cigarette smoke have been previously shown to cause widespread epigenetic changes, Bhide said.

“The fact that men smoke more than women makes the effects in males especially important from a public health perspective. Our findings underscore the need for more research on the effects of smoking by the father, rather than just the mother, on the health of their children.”

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Nutrition Has A Greater Impact On Bone Strength Than Exercise

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ANN ARBOR—One question that scientists and fitness experts alike would love to answer is whether exercise or nutrition has a bigger positive impact on bone strength. University of Michigan researchers looked at mineral supplementation and exercise in mice, and found surprising results–nutrition has a greater impact on bone mass and strength than exercise. Further, even after the exercise training stopped, the mice retained bone strength gains as long as they ate a mineral-supplemented diet.

“The longer-term mineral-supplemented diet leads to not only increases in bone mass and strength, but the ability to maintain those increases even after detraining,” said David Kohn, a U-M professor in the schools of dentistry and engineering.

“This was done in mice, but if you think about the progression to humans, diet is easier for someone to carry on as they get older and stop exercising, rather than the continuation of exercise itself.”

The second important finding is that the diet alone has beneficial effects on bone, even without exercising. This surprised Kohn, who expected exercise with a normal diet to fuel greater gains in bone strength, but that wasn’t the case.

“The data suggests the long-term consumption of the mineral-supplemented diet could be beneficial in preventing the loss of bone and strength with age, even if you don’t do exercise training,” he said.

Combining the two amplifies the effect.

Most other studies look at effects of increasing dietary calcium, Kohn said. The U-M study increased calcium and phosphorous, and found benefits to increasing both.

This isn’t to suggest that people run out and buy calcium and phosphorus supplements, Kohn said. The findings don’t translate directly from mice to humans, but they do give researchers a conceptual place to start.

It’s known that humans achieve peak bone mass in their early 20s, and after that it declines. The question becomes how to maximize the amount of bone when young, so that when declines do begin, people start from a better position, Kohn said.

In addition to testing bone mass and strength, Kohn and colleagues performed a full battery of mechanical assessments on the bone, which is important because the amount of bone doesn’t always scale with or predict the mechanical quality of the tissue.

They tested the mice after eight weeks of training and supplemented diet or normal diet, and then after eight weeks of detraining.

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