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Modifying a living genome with genetic equivalent of ‘search and replace’

Researchers including George Church have made further progress on the path to fully rewriting the genome of living bacteria. Such a recoded organism, once available, could feature functionality not seen in nature. It could also make the bacteria cultivated in pharmaceutical and other industries immune to viruses, saving billions of dollars of losses due to viral contamination.

Finally, the altered genetic information in such an organism wouldn’t be able to contaminate natural cells because of the code’s limitations outside the lab, researchers say, so its creation could stop laboratory engineered organisms from genetically contaminating wildlife. In the DNA of living organisms, the same amino acid can be encoded by multiple codons — DNA “words” of three nucleotide letters.

Here, building on previous work that demonstrated it was possible to use the genetic equivalent of “search and replace” in Escherichia coli to substitute a single codon with an alternative, Nili Ostrov, Church and colleagues explored the feasibility of replacing multiple codons, genome-wide.

The researchers attempted to reduce the number of codons in the E. coli code from 64 to 57 by exploring how to eradicate more than 60,000 instances of seven different codons. They systematically replaced all 62,214 instances of these seven codons with alternatives. In the recoded E.coli segments that the researchers assembled and tested, 63% of all instances of the seven codons were replaced, the researchers say, and most of the genes impacted by underlying amino acid changes were expressed normally.

Though they did not achieve a fully operational 57-codon E. coli, “a functionally altered genome of this scale has not yet been explored,” the authors write. Their results provide critical insights into the next step in the genome rewriting arena — creating a fully recoded organism.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/08/160818145954.htm  Original web page at Science Daily

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* Scientists test nanoparticle drug delivery in dogs with osteosarcoma

At the University of Illinois, an engineer teamed up with a veterinarian to test a bone cancer drug delivery system in animals bigger than the standard animal model, the mouse. They chose dogs — mammals closer in size and biology to humans — with naturally occurring bone cancers, which also are a lot like human bone tumors.

In clinical trials, the dogs tolerated the highest planned doses of cancer-drug-laden nanoparticles with no signs of toxicity. As in mice, the particles homed in on tumor sites, thanks to a coating of the drug pamidronate, which preferentially binds to degraded sites in bone. The nanoparticles also showed anti-cancer activity in mice and dogs.

The researchers report their results in the Proceedings of the National Academy of Sciences.

These findings are a proof-of-concept that nanoparticles can be used to target bone cancers in large mammals, the researchers said. The approach may one day be used to treat metastatic skeletal cancers, they said.

The dogs were companion animals with bone cancer that were submitted for the research trials by their owners, said U. of I. veterinary clinical medicine professor Dr. Timothy Fan, who led the study with materials science and engineering professor Jianjun Cheng. All of the dogs were 40 to 60 kilograms (88 to 132 pounds) in weight, he said.

“We wanted to see if we could evaluate these drug-delivery strategies, not only in a mouse model, but also at a scale that would mimic what a person would get,” Fan said. “The amount of nanoparticle that we ended up giving to these dogs was a thousand-fold greater in quantity than what we would typically give a mouse.”

Using nanoparticles with payloads of drugs to target specific tissues in the body is nothing new, Cheng said. Countless studies test such approaches in mice, and dozens of “nanopharmaceuticals” are approved for use in humans. But the drug-development pipeline is long, and the leap from mouse models to humans is problematic, he said.

“Human bone tumors are much bigger than those of mice,” Cheng said. “Nanoparticles must penetrate more deeply into larger tumors to be effective. That is why we must find animal models that are closer in scale to those of humans.”

Mice used in cancer research have other limitations. Researchers usually inject human or other tumor cells into their bodies to mimic human cancers, Fan said. They also are bred to have compromised immune systems, to prevent them from rejecting the tumors.

“That is one of the very clear drawbacks of using a mouse model,” Fan said. “it doesn’t recapitulate the normal immune system that we deal with every day in the person or in a dog.”

There also are limitations to working with dogs, he said. Dogs diagnosed with bone cancer often arrive at the clinic at a very advanced stage of the disease, whereas in humans, bone cancer is usually detected early because people complain about the pain and have it investigated.

“On the flip side of that, I would say that if you are able to demonstrate anti-cancer activity in a dog with very advanced disease, then it would be likely that you would have equivalent or better activity in people with a less advanced stage of the disease,” Fan said.

Many more years of work remain before this or a similar drug-delivery system can be tested in humans with inoperable bone cancer, the researchers said.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160725192351.htm Original web page at Science Daily

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Hybrid treatment hunts down and kills leukemia cells

Researchers at UC Davis and Ionis Pharmaceuticals have developed a hybrid treatment that harnesses a monoclonal antibody to deliver antisense DNA to acute lymphoblastic leukemia (ALL) cells and that may lead to less toxic treatments for the disease.

The study, published in the journal Molecular Medicine, demonstrated that once delivered, the therapeutic DNA reduced levels of MXD3, a protein that helps cancer cells survive. This novel conjugate therapy showed great promise in animal models, destroying ALL cells while limiting other damage.

“We’ve shown, for the first time, that anti-CD22 antibody-antisense conjugates are a potential therapeutic agent for ALL,” said Noriko Satake, associate professor in the Department of Pediatrics at UC Davis. “This could be a new type of treatment that kills leukemia cells with few side effects.”

ALL is the most common type of childhood cancer. It is a disease in which the bone marrow makes too many immature lymphocytes, a type of white blood cell. While most children survive ALL, many patients suffer late or long-term side effects from treatment, which may include heart problems, growth and development delays, secondary cancers and infertility.

Antisense oligonucleotides are single strands of DNA that can bind to messenger RNA, preventing it from making a protein. While antisense technology has long shown therapeutic potential, getting the genetic material inside target cells has been a problem.

In the study, researchers attached antisense DNA that inhibits the MXD3 protein to an antibody that binds to CD22, a protein receptor expressed almost exclusively in ALL cells and normal B cells.

Once the antibody binds to CD22, the conjugate is drawn inside the leukemia cell, allowing the antisense molecule to prevent MXD3 production. Without this anti-apoptotic protein, ALL cells are more prone to cell death.

The hybrid treatment was effective against ALL cell lines in vitro and primary (patient-derived) ALL cells in a xenograft mouse model. Animals that received the hybrid therapy survived significantly longer than those in the control group.

Designed to be selective, the treatment only targets cells that express CD22. While it does attack healthy B cells, the therapy is expected to leave blood stem cells and other tissues unscathed.

“You really don’t want to destroy hematopoietic stem cells because then you have to do a stem cell transplant, which is an extremely intensive therapy,” noted Satake. “Our novel conjugate is designed so that it does not harm hair, eyes, heart, kidneys or other types of cells.”

While the study shows the conjugate knocked down MXD3, researchers still have to figure out how this was accomplished. In addition, they will investigate combining this treatment with other therapies. Because it hastens cell death, the conjugate could make traditional chemotherapy drugs more effective. In addition, the approach might work against other cancers.

“You can see this as proof of principle,” Satake said. “You could switch the target and substitute the antibody, which could be used to treat other cancers or even other diseases.”

Access the full report at: http://static.smallworldlabs.com/molmedcommunity/content/pdfstore/15_210_Satake.pdf

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160728155631.htm  Original web page at Science Daily

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New signaling pathway for programmed cell death identified in leukemia cells

When adults develop blood cancer, they are frequently diagnosed with what is referred to as acute myeloid leukemia. The disease is triggered by pathological alterations of bone marrow cells, in which, in addition, an important mechanism is out of action: these cells do not die when they are damaged. Researchers from the Technical University of Munich (TUM) have now discovered a molecular signaling pathway for self-destruction that is suppressed in leukemia cells.

Leukemia involves pathological alterations in the body’s hematopoietic system. In acute myeloid leukemia, it is specifically the bone marrow (Greek: myelos) that is affected. In a healthy body, different blood cells, which perform different functions in the blood, are formed from stem cells and what is referred to as progenitor cells in the bone marrow. A genetic mutation can lead to alterations in stem cells and progenitor cells and turn them into leukemia-initiating cells, which are referred to as LICs for short. Like healthy progenitor cells, LICs multiply in the bone marrow. The genetic mutation, however, causes LICs to remain without function and prevents them from developing into mature blood cells, which ultimately leads to the repression of healthy hematopoiesis in the bone marrow and the onset of leukemia symptoms.

The most frequent genetic alterations in myeloid leukemia include mutations in the FLT3 gene. A team led by Dr. Philipp Jost from the Department of Hematology/Oncology at Klinikum rechts der Isar at the Technical University of Munich has now discovered that the effects of this gene on pathologically altered cells in a way provide certain indications for the treatment of the disease. The mutation causes a permanent activation of the FLT3 gene. As demonstrated by the scientists, this triggers inflammation-like stimuli in the cell, subjecting it to permanent stress.

Under normal circumstances, such permanent inflammatory stimuli would trigger a program known as programmed cell death to replace damaged cells. This is a kind of self-destruction mechanism used by a cell to initiate its own destruction in a coordinated fashion and allow it to be replaced by a healthy one. “By contrast, LICs manage to grow and proliferate despite the inflammation and damage,” states Philipp Jost. “In our study, we have taken a closer look at the molecular causes of this resistance.”

To gain a better understanding of the research project described by the TUM scientists in the medical journal “Cancer Cell,” it is important to understand that cells have different ways of self-destructing. So far, the primary research focus in trying to ascertain why cancer cells survive longer than they should has been placed on a process called apoptosis. However, the fact that inflammatory processes occur in LICs pointed Philipp Jost and his colleagues in a different direction. Another way to initiate cell death is through what is referred to as necroptosis. Whereas, in apoptosis, a cell shrinks in a coordinated fashion, in necroptosis, a sudden destruction occurs, which releases the contents of the dying cell along with numerous messenger substances. This induces a strong inflammatory stimulus in the vicinity of the cell.

Necroptosis is triggered by the activation of a protein called RIPK3, which subsequently initiates processes within the cell that lead to its death. The scientists used cell cultures to discover that leukemia takes a particularly severe course when RIPK3 is blocked inside LICs. This led to the cancer cells surviving particularly long, accompanied by their strong division and conversion to functionless blood cells (blasts). “We conclude from our findings that particularly aggressive cancer cells have the capacity to block RIPK3,” states Ulrike Höckendorf, lead author of the study. “Exactly how they accomplish this, however, remains to be investigated.”

Inducing cell death in a LIC by means of necroptosis has repercussions which also affect neighboring leukemia cells. The inflammatory stimuli triggered by the substances released during necroptosis are significantly stronger than the processes caused by the mutation in the FLT3 gene in a LIC. This inflammation has positive effects on the area surrounding the cell: induced by the messenger substances, neighboring leukemia cells begin to mature similar to healthy cells, leading to a less aggressive progression of leukemia.

With cell death blocked — apoptosis, too, is “neutralized” in many cancer cells — individual LICs manage to survive and proliferate even after chemotherapy or radiotherapy. “The new findings on the impact of the RIPK3 signaling pathway and the messenger substances released could open up new options for the treatment of leukemia,” states Philipp Jost. “If it were possible to artificially reproduce the effect of RIPK3 using medication, one could launch a targeted attack on leukemia cells.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/07/160714110910.htm Original web page at Science Daily

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Imaging technique could help focus breast cancer treatment

Cancer Research UK scientists have used imaging techniques as a new way to identify patients who could benefit from certain breast cancer treatments, according to a study published in Oncotarget.

The team at King’s College London, in collaboration with scientists at the CRUK/MRC Oxford Institute for Radiation Oncology, used fluorescence lifetime imaging to confirm if they have joined together.

Fluorescent lifetime imaging is a technique that can accurately measure the distance between two protein molecules. In this study the researchers measured the distance between HER2 and HER3 proteins in breast cancer cells from patients.

The researchers think that patients whose imaging results show that these proteins have bonded together could benefit from HER2 targeted treatment, regardless of whether their tumour has high levels of HER2.

HER2 is a protein which can cause cancer cells to grow. HER2-positive breast cancer cells have high levels of the protein and can be targeted with drugs that block its effects and stop the cancer from growing — drugs being used now include Herceptin and Tykerb. Patients who could benefit from these drugs are identified by testing their cancer cells to see if they show high levels of the HER2 protein.

But this imaging technique, carried out in tumour cells, could pick up additional patients in the future who would respond well to HER2-targeting drugs. It could also confirm which patients may not be suitable for these treatments.

Lead author, Professor Tony Ng, at King’s College London and University College London, said: “This imaging technique could help us pick up patients who might benefit from these drugs but have previously been overlooked.

“Using this test, we should be able to predict which drugs won’t work in patients and avoid prescribing unnecessary treatments — putting the drugs that we’ve got to better use. The next step is to run clinical trials to see if this test could help patients.

“We hope that one day it could not only improve treatment for breast cancer but also for other cancers — including bowel and lung cancer.”

Nell Barrie, senior science information manager at Cancer Research UK, said: “There are more than 50,000 new cases of breast cancer each year but thanks to advances in research, more people survive the disease than ever before. This research could eventually give doctors another way to personalise treatment so that patients receive the drugs that are most likely to help them.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/07/160707172030.htm Original web page at Science Daily

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* Infectious shellfish cancers may jump across species

Transmissible cancers have been found in shellfish, including cockles (Cerastoderma edule) collected in Galicia, Spain. Some clams, mussels and other bivalve molluscs carry infectious cancer cells that can leap between individuals — and that may even have jumped between species.

The discovery, reported on 22 June in Nature, means that transmissible tumours have now been found in six organisms. Two are well known in mammals: a facial tumour that threatens to wipe out Tasmanian devils (Sarcophilus harrisii) and a venereal cancer found in dogs all over the world.

“We thought these things happen now and then in nature, but that this was a fluke. Now, the finding that these seem to be fairly widespread in bivalves changes that outlook,” says Elizabeth Murchison, a molecular biologist at the University of Cambridge, UK, who studies the cancers prevalent in dogs and Tasmanian devils. The further finding that a cancer might have jumped between species is “shocking”, she says.

The latest work is led by virologist Stephen Goff of Columbia University in New York City, whose team last year found the first transmissible cancer among invertebrates — an edible soft-shell clam called Mya arenaria that lives in the tidal mudflats of the Atlantic, ranging from Canada to the southern United States.

Goff, who studies cancers caused by viruses, was looking for the source of a leukaemia common among clams, and discovered that tumours collected from animals in Long Island, Maine and Canada seemed to have the same genome sequence. “We were forced to come to the conclusion that somehow this clone had spread from animal to animal in the oceans up and down the coast,” he says.

After the discovery, Goff’s team reached out to marine biologists to see whether transmissible cancers were prevalent in other molluscs. In mussels (Mytilus trossulus) from British Columbia in Canada, and in cockles (Cerastoderma edule) and golden carpet-shell clams (Polititapes aureus) from the Galician coast in northwest Spain, the team found the same hallmarks of transmissible cancers: tumour cells from different individuals that shared the same genetic markers.

Two different lineages of cancers cells were found in infected cockles, which suggests that transmissible cancers emerged at least twice.

According to genetic analysis of the cancer DNA, the tumours in golden carpet-shell clams seemed to originate from another species of clam that lives in the same sea beds — the pullet shell clam (Venerupis corrugata).

“This is the first time that’s ever been seen,” says Goff. But peculiarly, Goff’s team found no signs of this cancer in the species in which it originated. It could be that the tumour wiped out vulnerable individuals in the original species, Goff suggests, and jumped to another species to find susceptible hosts.

Murchison says that the spreading of cancer between individuals requires the tumour to elude an immune attack, and she expects that the barrier is even higher between species. Clams have more-primitive immune systems than mammals, but Murchison still expects that transmissible tumours must overcome some level of resistance when moving within and between species.

Another mystery is how the cancer cells jump between individuals. Molluscs are voracious filter feeders, and the cancer cells floating around the ocean could make it to their bloodstream to seed new leukaemias. Tumour cells might be released when an animal dies, but Goff notes that the molluscs’ faeces are also full of blood cells. “It may just be that they’re pooping out these cells into the ocean,” he says.

Nature doi:10.1038/nature.2016.20138

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/infectious-shellfish-cancers-may-jump-across-species-1.20138  Original web page at Nature

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* Cancer-causing virus strikes genetically vulnerable horses

Sarcoid skin tumors are the most common form of cancer in horses, but little is known about why the papillomavirus behind them strikes some horses and not others. A new study by an international research group led by scientists at the Baker Institute for Animal Health at Cornell’s College of Veterinary Medicine shows genetic differences in immune function between horses partly accounts for these differences. The study, published in the International Journal of Cancer, mirrors findings in humans, as some people have a genetic susceptibility to human papillomavirus, which can cause cervical and other cancers.

“Many therapies have been proposed as the ‘best’ treatment for sarcoids,” says Dr. Doug Antczak, the Dorothy Havemeyer McConville Professor of Equine Medicine, who led the study. In some horses, tumors develop as small bumps under the skin or as scaly lesions that easily can be removed by a veterinarian, but in other horses the problem becomes much more serious. Surgery, cryotherapy (freezing the tissue), laser treatment, injecting the tumors with drugs to kill the cells, radiation treatment and immunotherapy have all been shown to cure these recalcitrant tumors, “but some tumors tend to recur no matter what treatment is used, and there is no universal consensus on a uniformly successful therapy,” says Antczak.

Antczak says it’s been thought for years that bovine papillomavirus (BPV) is the most likely culprit behind sarcoid tumors. Recent work from Europe suggests variants of the BPV have become adapted to horses and are probably the cause of most sarcoids.

With a grant from the Morris Animal Foundation, Antczak, his collaborators Samantha Brooks and Ann Staiger from the University of Florida, and the rest of the team applied a genomewide association study to compare the genetic makeup of horses with and without sarcoid tumors at more than 50,000 sites in the equine genome. They studied 82 sarcoid-bearing horses from the U.S. and United Kingdom and 272 carefully matched controls that did not have sarcoids. They found regions on chromosomes 20 and 22 that tended to be different in horses diagnosed with sarcoids, evidence that a horse’s genes determine, in part, how susceptible it is to sarcoids.

“This is an example of more complicated genetics — multigene susceptibility,” says Antczak. “More than one genetic region is associated with susceptibility to sarcoids, and they don’t completely determine whether or not a horse will develop the disease once it’s exposed to BPV.”

This genetic link implicates the immune system in sarcoid susceptibility. The region of chromosome 20 associated with sarcoid development is within a portion of the genome responsible for immune function called the Major Histocompatibility Complex (MHC) class II region. The MHC type associated with sarcoid susceptibility is very rare among Standardbred horses, a fact that may explain why sarcoid is diagnosed so rarely in this breed.

This complex mix of virus, host genes and tumor development may have relevance to a related human condition. Tumors caused by human papillomaviruses account for more than 5 percent of cancer cases worldwide. In women with cervical cancer, an association with the MHC class II region has also been shown.

“That should make a light bulb go off,” Antczak says. “It suggests there’s a common mechanism in both species for susceptibility to tumor progression that may involve subversion of the host immune response. By studying this phenomenon in horses you can learn about human cancer and vice versa.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/06/160610140652.htm  Original web page at Science Daily

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* Fighting cancer with the help of someone else’s immune cells

A new step in cancer immunotherapy: researchers from the Netherlands Cancer Institute and University of Oslo/Oslo University Hospital show that even if one’s own immune cells cannot recognize and fight their tumors, someone else’s immune cells might. Their proof of principle study is published in the journal Science on May 19th.

The study shows that adding mutated DNA from cancer cells into immune stimulating cells from healthy donors create an immune response in the healthy immune cells. Inserting the targeted components from the donor immune cells back into the immune cells of the cancer patients, the researchers were able to make cancer patients’ own immune cells recognize cancer cells.

The extremely rapidly developing field of cancer immunotherapy aims to create technologies that help the body’s own immune system to fight cancer. There are a number of possible causes that can prevent the immune system from controlling cancer cells. First, the activity of immune cells is controlled by many ‘brakes’ that can interfere with their function, and therapies that inactivate these brakes are now being tested in many human cancers. As a second reason, in some patients the immune system may not recognize the cancer cells as aberrant in the first place. As such, helping the immune system to better recognize cancer cells is one of the main focuses in cancer immunotherapy.

Ton Schumacher of the Netherlands Cancer Institute and Johanna Olweus of the University of Oslo and Oslo University Hospital decided to test whether a ‘borrowed immune system’ could “see” the cancer cells of the patient as aberrant. The recognition of aberrant cells is carried out by immune cells called T cells. All T cells in our body scan the surface of other cells, including cancer cells, to check whether they display any protein fragments on their surface that should not be there. Upon recognition of such foreign protein fragments, T cells kill the aberrant cells. As cancer cells harbor faulty proteins, they can also display foreign protein fragments — also known as neo-antigens — on their surface, much in the way virus-infected cells express fragments of viral proteins.

To address whether the T cells of a patient react to all the foreign protein fragments on cancer cells, the research teams first mapped all possible neo-antigens on the surface of melanoma cells from three different patients. In all 3 patients, the cancer cells seemed to display a large number of different neo-antigens. But when the researchers tried to match these to the T cells derived from within the patient’s tumors, most of these aberrant protein fragments on the tumor cells went unnoticed.

Next, they tested whether the same neo-antigens could be seen by T-cells derived from healthy volunteers. Strikingly, these donor-derived T cells could detect a significant number of neo-antigens that had not been seen by the patients’ T cells.

“In a way, our findings show that the immune response in cancer patients can be strengthened; there is more on the cancer cells that makes them foreign that we can exploit. One way we consider doing this is finding the right donor T cells to match these neo-antigens.,” says Ton Schumacher. “The receptor that is used by these donor T-cells can then be used to genetically modify the patient’s own T cells so these will be able to detect the cancer cells.”

“Our study shows that the principle of outsourcing cancer immunity to a donor is sound. However, more work needs to be done before patients can benefit from this discovery. Thus, we need to find ways to enhance the throughput. We are currently exploring high-throughput methods to identify the neo-antigens that the T cells can “see” on the cancer and isolate the responding cells. But the results showing that we can obtain cancer-specific immunity from the blood of healthy individuals are already very promising,” says Johanna Olweus.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160519144556.htm  Original web page at Science Daily

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Long-term survival achieved in metastatic melanoma with personalized vaccine

Robert O. Dillman, MD, formerly Vice President Oncology, Caladrius Biosciences, Inc. and currently Chief Medical Officer, NeoStem Oncology (Irvine, CA) and Executive Medical and Scientific Director, Hoag Cancer Institute (Newport Beach, CA) discusses the typically poor prognosis for patients with melanoma of the eye or skin that spreads to the liver, and reports on the potential to achieve long-term survival without disease progression in a subset of patients using the eltrapuldencel-T vaccine. One patient had no disease progression for more than 4.5 years, while the other patient survived and remained disease-free for more than 12 years.

The article “Long-term Progression-free and Overall Survival in Two Melanoma Patients Treated with Patient-Specific Therapeutic Vaccine Eltrapuldencel-T After Resection of a Solitary Liver Metastasis” provides a detailed discussion of the composition and use of the vaccine and its effectiveness in these patients.

“These exciting results illustrate the potential for melanoma patient-specific therapeutic vaccines to enhance long-term survival and add to the progress being made on the immmunotherapy of melanoma,” says Co-Editor-in-Chief Donald J. Buchsbaum, PhD, Department of Radiation Oncology, Division of Radiation Biology, University of Alabama at Birmingham.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/05/160510165122.htm Original web page at Science Daily

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Study of glioma susceptibility in dogs may yield insights for humans

A new study of the genetic factors underlying glioma formation in dogs may hold clues to how these common and often untreatable tumors form in humans. The genome study, which was conducted across 25 dog breeds, identified three genes associated with the tumor. The results from this research, led by Katarina Truvé of the Swedish University of Agricultural Sciences and Kerstin Lindblad-Toh of Uppsala University, were published on May 12 in PLOS Genetics.

Gliomas are the most common form of malignant primary brain tumors in humans and the second most common in dogs. Several dog breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, while certain related breeds do not, suggesting that a mix of genes may impact glioma formation. Dr Truvé says: “Researchers in the consortium are now continuing the analysis of the genes identified, and their functional roles in development and progression of glioma in both dogs and humans.”

To identify genetic variations that contribute to the tumor’s development, scientists performed a genome-wide association study (GWAS) using blood samples from 39 dogs diagnosed with glioma and 141 control dogs. By screening for variations commonly found in dogs that developed gliomas, they pinpointed three genes highly associated with susceptibility to the tumor: CAMKK2, P2RX7 and DENR.

Two of these genes have additional links to cancer. Further experiments by the scientists showed that both human and canine gliomas express CAMKK2 at lower levels than normal brain tissue, and previous studies have shown that a variation of P2RX7 reduces protein function in dogs while other variations have been identified in cancer patients. Future investigation of all three genes may yield a better understanding of the causes and potential treatments of glioma in both dogs and humans.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/05/160512145323.htm Original web page at Science Daily

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* Using precision-genetics in pigs to beat cancer

Pigs could be a valuable alternative to rodent models of cancer. The numbers are staggering: more than 40 % is the lifetime risk of developing cancer in the U.S., with only 66 % survival-rates 5 years after diagnosis, for all types of cancer. Trends suggest that in 2015, over 1.6 million new cases were diagnosed in the U.S., with over 580,000 deaths in consequence.

These numbers emphasize the need to better understand and treat the various forms of the disease, but mouse models usually used in cancer research have given us limited answers. However, Senior Scientist Adrienne Watson and colleagues at Recombinetics and the University of Minnesota, say that pigs may turn out to be the best alternative models.

“Many organ systems vary so greatly between rodents and humans that certain types of cancer cannot be accurately modelled,” says Watson, despite the major role mouse models have played in our understanding of the disease. The authors conclude that the five deadliest cancers in the U.S. cannot be modeled in rodents, or have ineffective models for identification of treatments that translate to the clinic.

Cancer is a genetic disease where cells acquire or inherit genetic mutations, which result in malfunctioning proteins that cause uncontrolled growth of cells in the blood or solid organs. “The anatomical, physiological, and genetic similarities between swine and humans are striking, suggesting that disease modeling in this large animal may better represent the development and progression of cancer seen in people.”

The authors explain, in their article that was published recently in Frontiers in Genetics, that new technology in precision-genetics, when applied to pigs, will lead the way, and could become especially advantageous when conducting targeted gene-editing using custom endonucleases, such as TALENs and CRISPRs, and transposon systems. “We can now engineer exact human disease alleles into the pig genome, to make novel models not available in rodents. They are incredibly valuable for their broader preclinical applications.”

Using genetically modified pigs would allow overcoming one of the main drawbacks of rodent models, which is their inability so far to identify safe and effective drugs to treat cancer. For example, the size and ease in handling pigs allows for drugs to be administered in the same way as in patients, and for follow up blood-work over time.

The authors caution that, as for any novel animal model to be useful in cancer research, it must be adopted and fully tested in many laboratories and under many circumstances. But the higher costs involved in handling these animals in the laboratory setting may be well worth the gains in our understanding of this deadly disease.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/05/160513111830.htm  Original web page at Science Daily

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Targeted missiles against aggressive cancer cells

Targeted missiles that can enter cancer cells and deliver lethal cell toxins without harming surrounding healthy tissue. This has been a long-standing vision in cancer research, but it has proved difficult to accomplish. A research group at Lund University in Sweden has now taken some crucial steps in this direction.

“For several years, we tried to elucidate which target proteins on the cancer cells’ surface can be used to help these ‘missiles’ to gain entry into cells. Developing this method has been complicated, and we feel pleased to finally have succeeded,” says Professor of Clinical Oncology Mattias Belting. His research group recently published this new method in Nature Communications.

Mattias Belting describes the interior of a cancer tumour as a hostile environment. The rapid cell division of the tumour leads to oxygen deficiency, low pH levels, and nutrient deprivation. In this environment, some cells die spontaneously, while others can be destroyed with the help of radiation, chemo- or immunotherapy. However, the cells that adapt and survive are particularly aggressive.

“We call them stressed cells, and they are known to be more aggressive and insensitive to regular cancer treatments. These are the ones we must find new ways to fight against,” explains Mattias Belting.

The Lund researchers have mapped the thousands of proteins that exist on the surfaces of regular cancer cells, and cells that are stressed due to lack of oxygen. They also found a special protein (caveolin-1) that serves as a gatekeeper, and prevents many of the surface proteins from entering stressed cancer cells.

The researchers continued with identifying some 30 targeted proteins that exist in large quantities on the surfaces of stressed cancer cells, and which also have the ability to effectively pass the “gatekeeper” and be transported into the cells. Against one of these proteins, they have successfully managed to target a toxin-conjugated missile, in the form of an antibody connected to a certain cell toxin, which was able to enter and kill stressed cells, while leaving other cells unharmed.

“The most important aspect of our results is not only that we have identified the proteins that exist on the stressed cancer cells, but also which of them can be used as targets for delivering drugs into the cells,” says first author of the study Erika Bourseau-Guilmain.

There has already been considerable interest in the group’s research. Their method and some of the target proteins are described in detail in the article in Nature Communications, enabling other researchers to build on the foundation laid by the research group from Lund.

“We want to continue to study other target proteins that were identified. We are currently studying other types of stress to find additional, potential target proteins for drug development,” says Mattias Belting.

The Lund researchers worked with cells from e.g. glioblastoma — a type of brain tumour that is difficult to treat. However, they believe that the “missile method” can be used not only against this type, but against many, if not all, types of solid cancers, as stressed cancer cells exist in all types of aggressive tumours.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/04/160420090110.htm  Original web page at Science Daily

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Researchers push for personalized tumour vaccines

It is precision medicine taken to the extreme: cancer-fighting vaccines that are custom designed for each patient according to the mutations in their individual tumours. With early clinical trials showing promise, that extreme could one day become commonplace — but only if drug developers can scale up and speed up the production of their tailored medicines.

The topic was front and centre at the American Association for Cancer Research (AACR) annual meeting in New Orleans, Louisiana, on 16–20 April. Researchers there described early data from clinical trials suggesting that personalized vaccines can trigger immune responses against cancer cells. Investors seem optimistic that those results will translate into benefits for patients; over the past year, venture capitalists have pumped cash into biotechnology start-ups that are pursuing the approach.

But some researchers worry that the excitement is too much, too soon for an approach that still faces many technical challenges. “What I do really puzzle at is the level of what I would call irrational exuberance,” says Drew Pardoll, a cancer immunologist at Johns Hopkins University in Baltimore, Maryland.

The concept of a vaccine to treat cancer has intrinsic appeal. Some tumour proteins are either mutated or expressed at different levels than in normal tissue. This raises the possibility that the immune system could recognize these unusual proteins as foreign — especially if it were alerted to their presence by a vaccine containing fragments of the mutated protein. The immune system’s army of T cells could then seek out and destroy cancer cells bearing the protein.

Decades of research into cancer-treatment vaccines have thus far yielded disappointing clinical trial results, but recent advances — including a suite of drugs that may amplify the effects of cancer vaccines — have rekindled hope for the field. And DNA sequencing of tumour genomes has revealed a staggering diversity of mutations, producing proteins that could serve as ‘antigens’ by alerting the immune system.

Last year, researchers reported that they had triggered an immune response in three patients with melanoma by administering a vaccine tailored to their potential tumour antigens. The vaccines’ effects on tumour growth are not yet clear, but by the end of 2015, several companies had announced their intention to enter the field. Gritstone Oncology, a start-up firm in Emeryville, California, raised US$102 million to pursue the approach, and Neon Therapeutics of Cambridge, Massachusetts, raised $55 million. A third company, Caperna, spun out of a prominent biotechnology company called Moderna Therapeutics, also in Cambridge.

Academic groups are also moving quickly. At the AACR meeting, Robert Schreiber of Washington University in St. Louis described six ongoing studies at his institution in cancers ranging from melanoma to pancreatic. Cancer researcher Catherine Wu of the Dana-Farber Cancer Institute in Boston, Massachusetts, also presented data from a trial in melanoma, showing signs of T-cell responses to the vaccine.

But it takes Wu’s team about 12 weeks to generate a vaccine, and the Washington University team needs about 8 weeks. That could limit the treatment to slow-growing cancers, says Wu.

There is also a reason that so many researchers choose melanoma for proof-of-principle trials. Melanoma tumours tend to harbour many mutations — sometimes thousands — which provide scientists with ample opportunity to select those that may serve as antigens. Some researchers worry that tumours with fewer mutations may not be as suitable for personalized vaccines.

But Schrieber notes that researchers have been able to design a vaccine for a woman with the brain tumour glioblastoma — which often has relatively few mutations. In that case, however, the tumour had many mutations, some of which may have been caused by her previous cancer treatment.

The number of potential antigens could be crucial. At the AACR meeting, Ton Schumacher, an immunologist at the Netherlands Cancer Institute in Amsterdam, noted that many of the mutant proteins that his group has found are not required for tumour survival. As a result, a tumour could maintain its cancerous lifestyle but become resistant to the vaccine if the proteins used to design the vaccine mutate again. “We will need to attack tumours from many different sides,” he says.

Pardoll, meanwhile, is concerned that the field is shifting too quickly to the personalized-vaccine approach and leaving behind decades of research on antigens that might be shared across tumours — an approach that has not borne out in clinical trials thus far, but would be much simpler to manufacture and deploy on a large scale. “I will be the happiest person in the world to be proven wrong on these,” he says of personalized vaccines. “But I think one has to nonetheless be cognizant of where the challenges are.”

Nature 532, 425 (28 April 2016) doi:10.1038/nature.2016.19801

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/researchers-push-for-personalized-tumour-vaccines-1.19801  Original web page at Nature

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Dressed to kill: Tailoring a suit for tumor-penetrating cancer medications

For more than a decade, biomedical researchers have been looking for better ways to deliver cancer-killing medication directly to tumors in the body. Tiny capsules, called nanoparticles, are now being used to transport chemotherapy medicine through the bloodstream, to the doorstep of cancerous tumors. But figuring out the best way for the particles to get past the tumor’s “velvet rope” and enter the tumor is a challenge scientists are still working out. Drexel University researchers believe that the trick to gaining access to the pernicious cellular masses is to give the nanoparticles a new look — and that dressing to impress will be able to get them past the tumor’s biological bouncers.

Targeted cancer therapy is most effective when the medication is released as close as possible to the interior of a tumor, to increase its odds of penetrating and killing off cancerous cells. The challenge that has faced cancer researchers for years is making a delivery vehicle that is sturdy enough to safely get the medication through the bloodstream to tumors — which is no smooth ride — but is also lithe enough to squeeze through the tumor’s dense extra cellular space — a matrix stuffed with sugars called hyaluronic acid.

In research recently published in the journal Nano Letters, lead author Hao Cheng, PhD, an assistant professor with an appointment in Drexel’s College of Engineering, and affiliation with School of Biomedical Engineering, Science and Health Systems; reports that the way to get past the tumor’s front door has everything to do with how the tiny particle is suited up for the journey.

“What we’ve reported here is a strategy to overcome biological barriers that plague delivery of medication, such as nonvehicle clearance in the bloodstream by the host immune system, and ineffective diffusion in the extracellular matrix of tumor cells,” Cheng said. “It’s a unique strategy that involves the decoration of nanovehicles with enzymes known to break down hyaluronic acid, which is a main barrier in the extracellular space, and the addition of an extra layer of polyethylene glycol to partially cover the enzymes.”

In the paper entitled “Hyaluronidase Embedded in Nanocarrier PEG Shell for Enhanced Tumor Penetration and Highly Efficient Antitumor Efficacy,” the group reports that their method is four times more effective at sending nanoparticles into a solid tumor than one of the best strategies currently in use. When cancer medication is loaded in the tiny particle, it has been shown to inhibit the growth of a type of aggressive breast cancer.

The team, which also included researchers Wilbur Bowne, MD, an associate professor in Drexel’s College of Medicine; Dimitrios Arhontoulis, an undergraduate in Drexel’s School of Biomedical Engineering, Science and Health Systems; lead author Hao Zhou and Zhiyuan Fan, doctoral candidates, Junjie Deng, PhD, postdoctoral researchers, and Pelin Lemons, a graduate student, all in the Materials Science and Engineering Department in the College of Engineering, created its nanoparticle suit by starting with one that is common in this area of cancer research and making some key alterations.

“In the general design of nanoparticles, bioactive molecules — not limited to enzymes — were attached on the outermost layer of particles,” Cheng said. “These enzymes can degrade the extra cellular matrix and enhance the nanoparticle’s ability to penetrate solid tumors.”

But in the body, this extra cargo can cause problems. One issue is that attaching enzymes to nanoparticles could cause them to come up short of the tumor and be cleared by the bloodstream before delivering the medication. There’s also a chance that the trip through the bloodstream could render the enzymes inert.

To counter these issues and keep the nanoparticles on course, the team decided to add an extra layer that not only protects the precious payload, but also positions the enzymes for maximum impact.

“The novelty of our design is that we partially embedded the hyaluronidase enzymes in a second polyethylene glycol layer to form the outer shell of the nanoparticle,” Cheng said. “This design dramatically reduces the enzymes’ effect on slowing the particle’s circulation and allows enzymes to maintain their function after the particle diffuses into the tumor.”

Embedding the enzymes in the layers of polyethylene glycol (PEG) ensures that the nanoparticle’s appearance tricks the immune system into leaving it alone during its trip to the tumor, yet and still allows the particle to deal with any hyaluronic acid it encounters on its penetration of the tumor. Other researchers have tested a theory that exposes tumors to the enzymes first, and then to nanoparticles, but this is not nearly as effective as Cheng’s method, because the nanoparticles developed at Drexel retain the enzymes through the duration of their diffusion into tumors, minimizing unnecessary hyaluronic acid degradation.

“The degradation of hyaluronic acid removes the barrier for nanoparticles to diffuse and allows them to access more cancer cells,” Cheng said. “The enhanced diffusion also increases the accumulation of nanoparticles in tumors, and the more nanoparticles that get into tumors the more effective they are at reducing its size.”

As part of the research, the team tested their nanoparticle against competitors that did not have a second layer of polyethylene glycol and ones that did not have the ECM-degrading enzymes. It was no surprise that their nanoparticle performed better in both penetrating tumors and accumulating in the cancerous cells.

“This exciting, novel nanoparticle drug delivery system will improve delivery of anti-cancer agents, enhancing anti-cancer activity to improve patient outcomes,” said Bowne. He foresees enormous potential for this strategy in the neoadjuvant and adjuvant setting for a number difficult to treat cancers such as locally advanced breast, pancreatic and mucin-producing gastrointestinal cancers.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/04/160408163824.htm  Original web page at Science Daily

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Radiation improves survival in older patients with soft tissue sarcomas

UC Davis researchers have shown that radiation therapy following surgery benefits older patients more than their younger counterparts, a surprising finding that could change the way some patients are treated for soft tissue sarcomas (STS).

The study, published in the journal Anticancer Research, used data from the Surveillance, Epidemiology, and End Results (SEER) program to assess whether radiation treatments after surgery improved disease-specific and overall survival in patients with non-metastatic sarcomas.

They found that radiation did increase survival compared to surgery alone, but the improvements mostly benefited patients 65 and older. This is the first time these outcomes have been analyzed on such a granular level, factoring in both age and cancer subtype.

“We found that older patients had a survival benefit with radiation, but in younger patients, many of those benefits went away,” said Robert Canter, associate professor in the Department of Surgery and principal investigator on the paper. “It seems that older patients respond better to the combination of surgery and radiation.”

There are more than 50 different types of soft-tissue sarcomas, which develop in muscles, fat and other cell types. While these conditions are generally treated surgically, it was not clear whether radiation therapy after surgery improved survival.

To clarify the issue, Canter and colleagues crunched data from SEER, which has gathered detailed cancer statistics since the 1970s. Analyzing data collected between 1990 and 2011, the team identified 15,380 non-pediatric patients with non-metastatic STS who were treated with surgery alone or with surgery and radiation.

The group pulled data on the tumor site, grade, size, cancer subtype and year of diagnosis, as well as the patient’s age, gender and other demographic information.

The team found significant improvements in overall survival and disease-specific survival in older patients across the majority of sarcomas. This was particularly true of the 12 major STS subtypes, including rhabdomyosarcoma, fibrosarcoma and synovial sarcoma. Younger patients benefited much less from radiation.

These results were somewhat surprising, as the researchers expected radiotherapy to primarily improve survival for younger patients.

“We were thinking it would be the opposite,” said Canter. “If the benefit is immune-mediated, younger patients should respond better since they have stronger immune systems.”

While younger patients did not receive the same level of benefit from radiotherapy as the older groups, they still had better overall and disease-specific survival from STS. The improvements among the older groups were compared to other older patients with similar disease who did not receive radiation.

Canter notes that more work must be done to validate the findings and illuminate the mechanisms that drive these age-related radiotherapy benefits. However, the work does offer a path to improve STS treatments for older patients.

“We sometimes don’t want to treat older people with radiation because we’re worried about the side effects,” said Canter. “However, these results indicate these patients should really be receiving it if they are candidates.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/04/160411134812.htm  Original web page at Science Daily

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Individualized cancer treatment targeting the tumor, not the whole body, a step closer

They look like small, translucent gems but these tiny ‘gel’ slivers hold the world of a patient’s tumour in microcosm ready for trials of anti-cancer drugs to find the best match between treatment and tumour.

The ‘gel’ is a new 3D printable material developed by QUT researchers that opens the way to rapid, personalised cancer treatment by enabling multiple, simultaneous tests to find the correct therapy to target a particular tumour.

Professor Dietmar W. Hutmacher from QUT’s Institute of Health and Biomedical Innovation said the new material was a gelatine-based hydrogel that mimicked human tissue. The method for producing the gelatine-based hydrogel is published in the journal Nature Protocols.

“Hydrogel is a biomaterial used by thousands of researchers around the globe; gelatine is based on collagen, one of the most common tissues in the human body. We have modified the gelatine to engineer 3D tumour microenvironments,” Professor Hutmacher said.

“Our big breakthrough is we can produce this high-quality material on a very large scale inexpensively.

“It is highly reproducible which means we have been able to produce this hydrogel hundreds of times, not just once or twice in the lab, so researchers worldwide will be able to create it.”

Professor Hutmacher said the new hydrogel could be used as a ‘bioink’ to print 3D ‘microenvironments’ or models of a tumour to test different anti-cancer drugs.

“We will be able to use this hydrogel infused with tumour cells to quickly create a number of models of patient-specific tumours.

“Instead of the sometimes hit and miss chemotherapy that affects every cell in the body this will allow us to test different anti-cancer drugs and different combinations of them all at once so that we can pinpoint an individualised treatment that will hit only the cancer cells.

“It will cut the process of finding a personalised treatment for each patient down to a week or two.” Because the hydrogel can be modified to mimic the firmness of cartilage or softness of breast tissue it can be used to create models for all types of cancer and also for research on stem cells and tissue engineering.

The IHBI research team includes Dr Daniela Loessner, Associate Professor Travis Klein and PhD student Christoph Meinert. The study, Functionalization, preparation and use of cell-laden gelatin methacryloyl-based hydrogels as modular tissue culture platforms was published this week.

The new hydrogel discovery is part of Biofabrication Research led by Professor Hutmacher at IHBI, which launched the world’s first Master of Biofabrication, a dual Australian and European master degree.

“We are seeking more students for the masters course at IHBI from all science and technology disciplines,” Professor Hutmacher says.

“Biofabrication is the future of medicine. It is a multidisciplinary area of research that requires an understanding of chemistry, physics, biology, medicine, robotics and computer science and we welcome graduates from any of these fields to apply for the master degree.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/03/160321110301.htm  Original web page at Science Daily

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New proteins discovered that link obesity-driven diabetes to cancer

For the first time, researchers have determined how bromodomain (BRD) proteins work in type 2 diabetes, which may lead to a better understanding of the link between adult-onset diabetes and certain cancers.

The findings, which appear in PLOS ONE, show that reducing levels in pancreatic beta cells of individual BRDs, called BET proteins, previously shown to play a role in cancer, may also help patients who are obese and diabetic.

The research was led by Gerald V. Denis, PhD, associate professor of pharmacology and medicine at Boston University School of Medicine, who was the first to show that BET protein functions are important in cancer development.

Adult-onset diabetes has been known for decades to increase the risk for specific cancers. The three main members of the BET protein family, BRD2, BRD3 and BRD4, are closely related to each other and often cooperate. However at times, they work independently and sometimes against each other.

According to the researchers new small molecule BET inhibitors have been developed that block all three BET proteins in cancer cells, but they interfere with too many functions.

“The BET proteins provide a new pathway to connect adult-onset diabetes with cancer, so properly targeting BET proteins may be helpful for both,” explained Denis, who is the corresponding author of the study.

He believes this discovery shows the need for deeper analysis of individual BET proteins in all human cell types, starting with boosting insulin and improving metabolism in the pancreas of adults who are obese.

“Without better targeted drugs, some ongoing cancer clinical trials for BET inhibitors are premature. These new results offer useful insight into drug treatments that have failed so far to appreciate the complexities in the BET family.”

https://www.sciencedaily.com/   Science Daily

https://www.sciencedaily.com/releases/2016/03/160323151852.htm  Original web page at Science Daily

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New clue to fighting acute myeloid leukemia found

A study led by researchers from the Cancer Science Institute of Singapore (CSI Singapore) at the National University of Singapore (NUS) has uncovered a new clue that may help fight acute myeloid leukemia (AML), the most common form of cancer of the blood and bone marrow, and an aggressive type of cancer. The findings open a new door to treating the disease more effectively.

AML usually originates from the bone marrow, where blood cells are produced. It is characterized by an overproduction of impaired white blood cells. The differentiation of immature white blood cell precursors into functional white blood cells is an essential process mediating the body’s immunity.

The research team found that an enzyme, GCN5, is able to inactivate a protein called C/EBPa in myeloid precursor cells. This prevents immature myeloid white blood cells from maturing into granulocytes — which make up about 70 per cent of white blood cells in the body. As a result, healthy white blood cells formation is disrupted.

The team, which includes Professor Daniel Tenen, Director of CSI Singapore, Ms Kwok Hui Si, PhD student at the Institute, as well as Dr Deepak Bararia, a former Postdoctoral Fellow at the Institute, discovered that the inactivation of the C/EBPa protein is carried out by acetylation, which is a process by which GCN5 adds an acetyl group onto C/EBPa reducing the ability of C/EBPa to bind to DNA and modulating its transcriptional activity in the cell. The findings of the study were published in the journal Nature Communications on 24 March 2016.

Identification of this molecular pathway provides clues towards targeting the GCN5-mediated acetylation of C/EBPa in the treatment of leukemia.

Prof Tenen said, “As AML is a fast-growing cancer, timely treatment soon after diagnosis could increase patients’ chances of survival. The current main treatment strategy for AML is cytotoxic chemotherapy. Our research results form the basis of an alternative therapeutic strategy that could potentially reduce remission risks and improve cure rates. Moving forward, the team is looking into designing effective GCN5 inhibitors for therapeutic purposes by studying GCN5 in AML further in depth.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/03/160329101534.htm  Original web page at Science Daily

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Fat mice provide clue to obesity-colon cancer puzzle

Obese mice — like obese humans — are at increased risk of colon cancer, and a study published today in Nature finally suggests why. Overweight mice fed a high-fat diet showed an increase in intestinal stem cells due to activation of a protein called PPAR-δ that regulates metabolism.

If the results hold true in humans, they could explain a phenomenon seen in epidemiological studies. “For quite some time there’s been an understanding that obesity leads to an increase in cancer in many tissues,” says Ömer Yilmaz, a cancer biologist at the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT) in Cambridge, and one of the leaders of the study. “We really wanted to understand the mechanism behind this.”

Those molecular details could be important, says cell biologist P. Kay Lund who works at the University of North Carolina in Chapel Hill and the National Institutes of Health in Bethesda, Maryland. Tissue samples from people who have undergone colonoscopies could be tested to see if the same patterns hold true. Ultimately, the increase in PPAR-δ activity could yield a useful indicator of cancer risk. “It could provide an opportunity to give those patients an earlier intervention,” says Lund, who was not involved in the obesity work.

Yilmaz teamed up with David Sabatini, who studies metabolism at MIT and the Whitehead Institute, also in Cambridge, to learn more about the link between cancer and obesity. Their teams fed mice high-fat, high-calorie chow for about a year, and then tested the effects of the diet on the number and function of stem cells in their intestines.

They found that the diet, which was 60% fat, not only led the mice to overeat and become overweight, it also activated PPAR-δ and stimulated the proliferation of intestinal stem cells. Treating the mice with a drug that activates PPAR-δ yielded similar cellular regeneration. Stem cells are thought to be more likely to give rise to tumours than other cell types.

For now, it is not clear whether the changes in the mice are due to weight gain — and the metabolic changes that come with it — or to fatty food. The team also tested the response of intestinal cells grown in three-dimensional cultures called ‘organoids’, to fatty acids found in the high-fat chow. Those cells also activated PPAR-δ, suggesting that the fatty acids may have been acting directly on its expression.

If so, it could be “a mechanism in search of a relation that doesn’t exist in humans”, cautions Walter Willett, who studies nutrition at the Harvard T.H. Chan School of Public Health in Boston, Massachusetts. Greater body fat in humans has been linked to increased cancer risk, he says, but there is no firm evidence of a relationship between a fatty diet and cancer in humans, despite intensive study.

But Yilmaz notes that epidemiological studies can be muddled by confounding variables. ”The data linking fat intake to cancer incidence is a mixed bag,” he says. Yilmaz’s team hopes to pick apart the role of fatty acids in cancer risk by conducting follow-up studies in normal-weight mice fed high-fat chow.

Nature doi:10.1038/nature.2016.19484

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/fat-mice-provide-clue-to-obesity-colon-cancer-puzzle-1.19484 Original web page at Nature

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Breast cancer: An improved animal model opens up new treatments

EPFL scientists have developed an animal model for breast cancer that faithfully captures the disease. Tested on human breast tissue, this the most clinically realistic model of breast cancer to date.

Breast cancer is the most common cause of cancer-related deaths worldwide, affecting one in eight women. There are different types of breast cancer, but one type in particular accounts for almost three quarters of all breast tumors. These tumors feature a receptor for estrogen, and very often become resistant to hormone therapy. Despite their high frequency, these “estrogen receptor-positive” tumors have been difficult to research because the animals we test drugs on are often not relevant to the clinic. Publishing in Cancer Cell, EPFL scientists have now developed the most biologically faithful animal model for estrogen receptor-positive breast cancer. Their model has also been tested on human breast tissue in a pre-clinical context.

About 90 percent of tested new cancer drugs fail. The reason, in part, is that the animals on which these drugs are tested often fail to capture the complex biology of the cancers they are meant to represent. This biological inaccuracy frequently gives rise to data that seem encouraging at first but are then not matched in humans. The drug fails and pushes research back to square one.

Some of the best pre-clinical animal models for breast cancer are made by injecting human breast tumors into the fatty tissue of the animal’s breast or its flank — the animal itself is usually a mouse. Nevertheless, these animal models — called “patient-derived xenografts” — under-represent the most frequent and lethal breast tumors, the estrogen receptor-positive type. The reason is that after injection into the animal, the tumor cells frequently die off and fail to proliferate.

The lab of Cathrin Brisken at EPFL has now developed the first xenograft to better represent the biology of estrogen receptor-positive breast tumors in humans. Postdoc George Sflomos and colleagues show that the mouse’s milk ducts are the key for the physiological growth of estrogen receptor-positive breast tumors, as they offer the injected cells a more suitable environment to grow and proliferate in rather than the conventional routes (the mammary fat pad and the flank). By injecting cells from an estrogen receptor-positive tumor into the mouse’s milk ducts, the researchers could improve the survival rate of the tumor cells for the first time ever.

To test their new xenograft idea, the team obtained breast cancer cell lines and tumor tissues from estrogen receptor-positive breast cancer patients, and injected them directly into the milk ducts of mice. The results were remarkable: All the new xenograft models that were tested faithfully mimicked actual patient tumors in terms of histopathology and even molecular biology.

“With this breakthrough, breast cancer disease, progression and metastasis, now become amenable to study,” says Sflomos. “We can now study crucial factors, such as the action of hormones and molecular responses to therapies, for the first time in a relevant context. But more importantly, this model opens up new opportunities not only for the development but also for the evaluation of breast cancer therapies.”

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/03/160303132955.htm Original web page at Science Daily

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Cancer cells eat their neighbors’ ‘words’

Cancer cells are well-known as voracious energy consumers, but even veteran cancer-metabolism researcher Deepak Nagrath was surprised by their latest exploit: Experiments in his lab at Rice University show that some cancer cells get 30-60 percent of their fuel from eating their neighbors’ “words.”

“Our original hypothesis was that cancer cells were modifying their metabolism based on communications they were receiving from cells in the microenvironment near the tumor,” said Nagrath, assistant professor of chemical and biomolecular engineering at Rice and co-author of a new study describing the research in the open-access journal eLife. “None of us expected to find that they were converting the signals directly into energy.”

The results were part of a four-year study by Nagrath, his students and collaborators at the University of Texas MD Anderson Cancer Center and other institutions about the role of exosomes in cancer metabolism. Exosomes are tiny packets of proteins, microRNA and nucleic acids that cells emit into their environment to both communicate with neighboring cells and influence their behavior. Nagrath, who directs Rice’s Laboratory for Systems Biology of Human Diseases, found that some cancer cells are capable of using these information packets as a source of energy to fuel tumor growth.

His work is the latest in a series of discoveries about cancer metabolism that date to German chemist Otto Warburg’s 1924 discovery that cancer cells produce far more energy from the metabolic process known as glycolysis than do normal cells. The Nobel Prize-winning discovery of the “Warburg effect” led scientists to believe, for decades, that all cancers were dependent on glycolysis. Nagrath’s lab and others have shown in recent years that the truth is far more complex: Each type of cancer has a unique metabolic profile. Nagrath’s work aims at better understanding those profiles and their role in cancer metastasis and drug resistance, and he ultimately hopes to use the knowledge to develop more effective cancer treatments.

In a May 2014 study, Nagrath and colleagues found that highly aggressive ovarian cancer cells were glutamine-dependent and that depriving the cells of external sources of glutamine — as some experimental drugs do — was an effective way to kill late-stage ovarian cancer cells in the lab. And a December 2014 study found that ovarian tumors coax adult stem cells into providing key metabolites they need to grow.

The exosome study began four years ago based upon a growing realization that exosomes might play a role in regulating cancer metabolism.

“A growing body of evidence suggests that exosomes can facilitate crosstalk between cancer cells and other types of cells that are nearby in the microenvironment that surrounds the tumor,” said Hongyun Zhao, the first author of the eLife study. “Some studies suggested that exosomes harbored the potential to regulate cancer cell metabolism, but most research had focused on the exosomes that were produced and emitted by cancer cells themselves. We decided to look at the exosomes of stromal cells, a type of cell that is commonly found in the tumor microenvironment, and see if stromal exosomes were influencing the energy consumption of cancer cells.”

Zhao’s first experiments involved growing cultures of stromal cells, extracting their exosomes and exposing them to cancer cells, which were then monitored for metabolic changes. Nagrath said the tests suggested that the cancer was fueling itself by consuming amino acids directly from the exosomes, and a series of monthslong follow-up tests had to be conducted to rule out other possibilities.

“Our results show that not only do exosomes enhance the phenomenon of the ‘Warburg effect’ in tumors, but exosomes also contain ‘off-the-shelf’ metabolites within their cargo that cancer cells use directly in their metabolic processes,” Zhao said.

Nagrath said some of Zhao’s follow-up tests also suggest possible new treatment regimes. For example, in some tests, Zhao exposed cancer cell cultures to drugs that were known to block the uptake of exosomal signals. The tests, which showed that the cancer cell’s metabolic activity dropped significantly, helped prove that the tumors were using the exosomes as fuel. The fact that four of the drugs used in the tests — heparin, cytochalasin D, ethyl-isopropyl amiloride and choloroquine — are already approved by the Food and Drug Administration for other uses suggests that they may also be useful as chemotherapeutic agents, Nagrath said.

“Disruption of the exosomal metabolic adaptation of cancer cells could provide a novel therapeutic avenue for exploitation,” he said.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/03/160307150246.htm  Original web page at Science Daily

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* Groundbreaking discovery made use skin cells to kill cancer

Skin cells turned cancer-killing stem cells hunt down, destroy deadly remnants inevitably left behind when a brain tumor is surgically removed

In a first for medical science, University of North Carolina at Chapel Hill pharmacy researchers turn skin cells into cancer-hunting stem cells that destroy brain tumors known as glioblastoma — a discovery that can offer, for the first time in more than 30 years, a new and more effective treatment for the disease.

The technique, reported in Nature Communications, builds upon the newest version of the Nobel Prize-winning technology from 2007, which allowed researchers to turn skin cells into embryonic-like stem cells. Researchers hailed the possibilities for use in regenerative medicine and drug screening. Now, researchers have found a new use: killing brain cancer.

“Patients desperately need a better standard of care,” said Shawn Hingtgen, Ph.D., an assistant professor in the UNC Eshelman School of Pharmacy and member of the Lineberger Comprehensive Care Center, who led the study.

The survival rate beyond two years for a patient with a glioblastoma is 30 percent because it is so difficult to treat. Even if a surgeon removes most of the tumor, it’s nearly impossible to get the invasive, cancerous tendrils that spread deeper into the brain and inevitably the remnants grow back. Most patients die within a year and a half of their diagnosis.

Hingtgen and his team want to improve those statistics by developing a new personalized treatment for glioblastoma that starts with a patient’s own skin cells, with the goal of getting rid of the cancerous tendrils, effectively killing the glioblastoma.

In their work, Hingtgen and his team reprogram skin cells known as fibroblasts — which produce collagen and connective tissue — to become induced neural stem cells. Working with mice, Hingtgen’s team showed that these neural stem cells have an innate ability to move throughout the brain and home in on and kill any remaining cancer cells. The team also showed that these stem cells could be engineered to produce a tumor-killing protein, adding another blow to the cancer.

Depending on the type of tumor, the Hingtgen’s team increased survival time of the mice 160 to 220 percent. Next steps will focus on human stem cells and testing more effective anti-cancer drugs that can be loaded into the tumor-seeking neural stem cells.

“Our work represents the newest evolution of the stem-cell technology that won the Nobel Prize in 2012,” Hingtgen said. “We wanted to find out if these induced neural stem cells would home in on cancer cells and whether they could be used to deliver a therapeutic agent. This is the first time this direct reprogramming technology has been used to treat cancer.”

Hingtgen’s team is also currently improving the staying power of stem cells within the surgical cavity. They discovered that the stem cells needed a physical matrix to support and organize them, so they will hang around long enough to seek out the cancerous tendrils. “Without a structure like that, the stem cells wander off too quickly to do any good,” said Hingtgen, who reported this result in a separate journal called Biomaterials.

In that study, Hingtgen and his team added his stem cells to an FDA-approved fibrin sealant commonly used as surgical glue. The physical matrix it creates tripled the retention of stem cells in the surgical cavity, providing further support for the applicability and strength of the technique.

https://www.sciencedaily.com/  Science Daily

https://www.sciencedaily.com/releases/2016/02/160224151404.htm  Original web page at Science Daily

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Potential therapy for most aggressive type of lung cancer in preclinical models

Lung cancer is one of the most prevalent types of cancer, with more than 20,000 new cases diagnosed each year in Spain. Lung adenocarcinomas carrying oncogenic KRAS, the engine driving these tumours in 30% of cases, constitute the most aggressive sub-type because, unlike other types of lung cancer, there are no targeted therapies beyond the standard cisplatin-based treatment.

Researchers of the Experimental Oncology Group at the Spanish National Cancer Research Centre (CNIO), headed by Mariano Barbacid, director of the Group, and the researcher David Santamaría, will be publishing a paper in the journal Nature Medicine this week explaining how the combination of dasatinib — DDR1 protein inhibitor — and demcizumab — a Notch pathway inhibitor antibody — specifically and effectively reduces lung adenocarcinomas and improves prognosis and survival rates substantially. Once the preclinical studies have been completed, “the next step in this research would be the clinical trials to validate the combination of these drugs as the first therapy directed against these aggressive tumours,” says Chiara Ambrogio, first author of the paper.

One of the most important barriers in the study of lung adenocarcinomas is their great heterogeneity when they reach advanced stages: tumour cells evolve over time, learn to adapt to the environment in order to grow and survive and form sub-populations within the same tumour. This heterogeneity explains why many patients stop responding to cancer treatments.

“Classically, tumours have been studied at advanced stages, but we were interested in studying the initial stages of tumour formation. We followed this approach to avoid the heterogeneity issue and try to identify new essential mechanisms that sustain tumour development with potential therapeutic uses,” says Ambrogio.

The researchers analysed the gene signature of these tumours through large-scale gene analysis techniques. “We discovered that these tumours display high levels of activity of the DDR1 gene, so we decided to validate its inhibition as a potential therapeutic strategy for this type of tumour.”

Recent data indicate that combined therapies using two or more drugs can prevent, or at least delay, relapses in the case of cancer patients; thus, the experts simultaneously used dasatinib, which inhibits the DDR1 protein, together with demcizumab, an antibody inhibiting the Notch pathway that is functionally related to DDR1 in this tumour type.

After five years of research, the experts conclude that the combination of the two drugs has additive effects on tumours, reducing their size, preventing their progression and significantly increasing survival rates. “One of the advantages of the project is that the two drugs employed have already been approved by the regulatory agencies, which will significantly speed-up studies on human patients. The next steps are clinical trials to validate the combination of these drugs as the first targeted therapy for the treatment of these tumours.”

The authors of the paper have used preclinical models of genetically modified mice. In collaboration with the team of Alberto Villanueva in the Catalan Institute of Oncology (ICO), they generated orthotopic mouse models by implanting lung tumours from patients in order to validate the effectiveness of the drugs directly on human samples. The teams of Manuel Serrano and Manuel Hidalgo from the CNIO have also participated in the study.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2016/02/160211142232.htm  Original web page at Science Daily

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* Molecular processes for targeted dog cancer therapy investigated

Dogs get cancer, just like humans. Scientists at the University of Veterinary Medicine, Vienna are now exploring the molecular basis of cancer progression in canine cell lines. Modern cancer therapy has been revolutionized with the introduction of new drugs, so-called ‘targeted drugs’, but the basis for the application of these new agents in cancer therapy is a deep understanding of the molecular mechanisms of the disease, even with pets. Now a research team led by Sabine Macho-Maschler has investigated the activation of genetic regulatory mechanisms in canine cells and found both matches as well as differences compared to humans.

Almost every second dog above the age of ten years develops cancer. Modern tumor therapy combines surgery, radiation therapy and novel drug treatment options. While surgery and radiotherapy ensure adequate treatment for all animals at the University of Veterinary Medicine, Vienna, there is a growing gap in the treatment with modern therapeutics. The reason for this is that modern targeted agents are based on specific molecular genetics findings, which are not easy to transfer to dogs from humans or the preferred animal model in cancer research, the mouse. So to make modern cancer drugs also accessible to our four-legged friends requires comparative research into the molecular basis of cancer in dogs.

Our understanding of the molecular and cellular causes that are responsible for the development of cancer has grown strongly in recent years. This knowledge aids us in combating cancer cells with a growing number of new drugs. However, since cancer may manifest itself differently in each patient, an extensive molecular study of the existing mutations in cancer cells is an important prerequisite for successful therapy. This is because the targeted agents can only actually help when the cancer cells possess the corresponding molecular structures against which the drug is designed to act. The success of treatment with targeted drugs requires a molecular diagnosis, as basis for the so-called ‘personalized medicine’ in cancer research.

A research team at the Unit of Molecular Genetics have investigated an important process in the molecular genetics of cancer development in canine cell lines. These cell lines have long been used by researchers to analyze pathological processes and now were analyzed for changes in the expression of several RNA-species using next generation sequencing. “Cancer researchers have been working for many years on the transition of epithelial tumor cells into the more aggressive mesenchymal state. Important gene switches could be identified in this process with potential for use as therapeutic targets: these gene products could be targeted with novel therapeutics,” explained Macho-Maschler, who headed the now published study.

Research on epithelial-mesenchymal transition (EMT) has so far mainly focused on cells of mice and humans and showed how certain signaling pathways cooperate to allow cancer cells metastasis. Metastases are formed when the originally sedentary cancer cells obtain certain properties, which allow them to migrate into another organ and to form a new tumor there. “In the majority of cases it is the metastases that cost the patient’s live, as the original tumor can often be well controlled by radiation and surgery,” emphasized Mathias Müller, head of the Institute for Animal Breeding and Genetics. “We are interested in what is going on at the molecular level during metastasis, as it is likely that we can use this knowledge for the successful treatment of metastases.”

The molecular analysis of EMT is considered by researchers as a model for the acquisition of the ability to metastasize. The TGF-beta pathway has for a long time been recognized as a central switch in this process. Macho-Maschler expressed her satisfaction with the many similarities seen in the comparative analysis of results for canine, human and mouse cells. “TGF-beta, for example, also plays an important role in dogs, but there are also interesting variations,” reports Macho-Maschler. Her recent BMC Genomics publication is filled with long lists of RNAs that are regulated during EMT. These findings should serve as a basis for further analysis. Macho-Maschler is skeptical as to whether their research can improve the treatment of dogs with cancer in the near future. “Our newly published results are like a catalogue, perhaps an important requirement for new approaches and ideas. Ultimately, we do not even know whether many of the new drugs actually act in canine cells. There are, for example, targeted drugs which act only in humans but not in mice” says Macho-Maschler to dampen unrealistic expectations. In humans, a much more comprehensive catalogue was completed this year; “The Cancer Genome Atlas” makes available to researchers the essential information contained within 11,000 genetically analyzed patient samples (cancergenome.nih.gov). It is an important resource, which enables researchers quickly and reliably to check the frequency of certain genetic changes in a cancer. The catalogue published by Macho-Maschler is naturally not comparable with the TCGA, but it is a first important step in the same direction for canine cancer.

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/12/151204094354.htm  Original web page at Science Daily

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Novel RNA delivery system may treat incurable blood cancers

With a median survival rate of just five to seven years, Mantle Cell Lymphoma (MCL) is considered the most aggressive known blood cancer — and available therapies are scarce. Three thousand Americans are diagnosed with MCL every year, and despite progress in personalized therapies to treat metastases elsewhere in the body, systemic therapeutic drug delivery to cancerous blood cells continues to challenge the world of cancer research.

A new study by Tel Aviv University researchers offers tangible hope of curing the currently incurable blood cancer — and others like it. The revolutionary system was found to successfully halt the proliferation of a cancer-related protein in white blood cells in both animal models and samples taken from MCL patients.

The research was led by Prof. Dan Peer of TAU’s Department of Cell Research and Immunology and conducted by TAU PhD students Shiri Weinstein and Itai Toker, in collaboration with Prof. Pia Raanani of Rabin Medical Center and Prof. Arnon Nagler of Sheba Medical Center. The study was published in the early edition of the Proceedings of the National Academy of Sciences(PNAS).

“MCL has a genetic hallmark,” said Dr. Peer. “In 85 percent of cases, the characteristic that defines this aggressive and prototypic B-cell lymphoma is the heightened activity of the gene CCND1, which leads to the extreme overexpression — a 3,000- to 15,000-fold increase — of Cyclin D1, a protein that controls the proliferation of cells. Downregulation of Cyclin D1 using siRNAs is a potential therapeutic approach to this malignancy.”

The research validates a novel strategy developed two years ago in Dr. Peer’s lab that involved small interfering RNAs (siRNAs). The radical new delivery system harnesses nanoparticles coated with “GPS” antibodies that navigate toward the location of the cancerous cells, where they then offload Cyclin D1-blockers in the form of siRNAs.

For the purpose of the research, the scientists designed lipid-based nanoparticles (LNPs) coated with anti-CD38 monoclonal antibodies that were taken up by human MCL cells in the bone marrow of affected mice. When loaded with siRNAs against Cyclin D1, the targeting LNPs induced gene silencing in MCL cells and prolonged the survival of tumor-bearing mice with no observed adverse effects.

“In MCL, Cyclin D1 is the exclusive cause of the over-production of B Lymphocytes, the cells responsible for generating antibodies,” said Dr. Peer. “This makes the protein a perfect target for RNA therapy by siRNAs. Normal, healthy cells don’t express the gene, so therapies that destroy the gene will only attack cancer cells. The RNA interference we have developed targets the faulty Cyclin D1 within the cancerous cells. And when the cells are inhibited from proliferating, they sense they are being targeted and begin to die off.”

The new research highlights the therapeutic potential of Cyclin D1 therapy in MCL and presents a novel RNA delivery system that opens new therapeutic opportunities for treating MCL and other similar B-cell malignancies.

“This research makes a definite contribution to the revolution of personalized medicine, whereby you tailor the drug based on the genetic profile of patient,” said Dr. Peer. “In this case, MCL is a disease with a specific genetic hallmark, so you can sequence the patient to identify the mutation(s), and design RNA blockers to be placed inside a nanovehicle.

“While the targeting antibodies — the ‘GPS’ — can be used to target many different B-cell malignancies, the drug itself is designed to silence this specific disease. However, the delivery system can be used to accommodate any disease with a genetic profile. This could be the future. We are seeing it happen before our very eyes.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2016/01/160105133130.htm  Original web page at Science Daily

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DNA repair enzyme identified as a potential brain cancer drug target

Rapidly dividing cells rely on an enzyme called Dicer to help them repair the DNA damage that occurs as they make mistakes in copying their genetic material over and over for new cells. UNC Lineberger Comprehensive Cancer Center researchers have built on the discovery of Dicer’s role in fixing DNA damage to uncover a new potential strategy to kill rapidly dividing, cancerous cells in the brain.

In the journal Cell Reports, researchers report that when they removed Dicer from preclinical models of medulloblastoma, a common type of brain cancer in children, they found high levels of DNA damage in the cancer cells, leading to the cells’ death. The tumor cells were smaller, and also more sensitive to chemotherapy.

“This is the first time that the specific function of Dicer for DNA damage has been looked at in the context of the developing brain or even in brain tumors, despite that the fact that the protein has been extensively studied,” said Mohanish Deshmukh, PhD, a UNC Lineberger member and professor in the UNC School of Medicine Department of Cell Biology and Physiology and also the Neuroscience Center. “We have found that targeting Dicer could be an effective therapy to either prevent cancer development or to actually sensitize tumors to chemotherapy.”

Scientists have understood for more than a decade that Dicer plays an important role in the cell for processing microRNAs, which regulate the expression of genes in cells. But Deshmukh said it was in 2012 that scientists discovered a direct role of Dicer in repairing DNA damage. And that function, he said, is of importance for cancer research. That’s because rapidly dividing cells — such as cancer cells — incur DNA damage as they divide. And chemotherapy and radiation treatments often work by damaging the cells’ DNA, leading to cell death. Removing a key enzyme that repairs DNA in cancerous cells could help prevent DNA repair.

“We found that cancerous cells upregulate Dicer,” said Vijay Swahari, MBBS, MS, a postdoctoral fellow at the UNC Neuroscience Center and the first author of this study. “We think tumors upregulate Dicer because its function is to repair DNA.”

In their study, Deshmukh and his team studied the effect of deleting Dicer in several types of rapidly dividing cells, including of preclinical brain cancer models. They deleted Dicer in the normal, rapidly dividing developing brain cells in the cerebellum of animal models, finding spontaneous DNA damage in the brain cells, leading to severe degeneration of the cerebellum. They also tested whether Dicer had a similar effect on rapidly dividing cells outside of the brain. Upon deleting Dicer from embryonic stem cells, the authors found a similar effect.

To test whether they could exploit the role of Dicer to kill cancerous cells, Swahari and his collaborators also deleted Dicer in medulloblastoma models, and found that these cells also had high DNA damage levels and degeneration. The tumor load was lower, and the cells were more sensitive to chemotherapy.

“We found that when you delete Dicer, these tumors are more sensitive to DNA damage,” Swahari said. “We also took the next step by injecting chemotherapy into models where Dicer was deleted, finding that not only are the tumors smaller, but the tumors are also more sensitive to chemotherapy.”

Based on their findings, the researchers believe that Dicer could be investigated as a potential drug target for medulloblastoma and other types of brain cancer. “We are excited about these results because of the implication that Dicer inhibitors could be developed as a potential therapy for treating rapidly-dividing tumors like medulloblastoma,” Deshmukh said.

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http://www.sciencedaily.com/releases/2016/01/160105112336.htm  Original web page at Science Daily

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Endangered foxes on Catalina Island get promising treatment to reduce ear tumors

A team of scientists led by UC Davis found alarming rates of ear mites and ear canal tumors in the endangered foxes. Ear mite treatments they initiated have since dramatically reduced the problem, their studies show.

Until recently, endangered foxes on California’s Catalina Island were suffering from one of the highest prevalences of tumors ever documented in a wildlife population, UC Davis scientists have found. But treatment of ear mites appears to be helping the wild animals recover. Roughly half of adult foxes examined between 2001 and 2008 had tumors in their ears, with about two-thirds of those malignant, according to a UC Davis study published this month in the journal PLOS ONE.

More than 98 percent of the foxes were also infected with ear mites. These mites appear to be a predisposing factor for ear tumors in the Santa Catalina Island fox. “We established a high prevalence of both tumors and ear mites, and hypothesized that there was something we could potentially do about it, which now appears to be significantly helping this population,” said Winston Vickers, lead author of the prevalence study and an associate veterinarian with the UC Davis Wildlife Health Center at the UC Davis School of Veterinary Medicine.

Working closely with researchers from the Institute for Wildlife Studies and Catalina Island Conservancy, the scientists conducted one of the few studies to estimate disease prevalence in an entire free-living wildlife population.

A complementary study, also led by UC Davis and published in PLOS ONE today, found that treatments with acaracide, a chemical agent used to kill ear mites in dogs and cats, reduced the prevalence of ear mite infection dramatically, from 98 percent to 10 percent among treated foxes at the end of the six-month trial. Ear canal inflammation and other signs of developing ear tumors also dropped.

“It’s rare to have a success story,” said the ear mite study’s lead author, Megan Moriarty, a student with the UC Davis School of Veterinary Medicine when the study began and currently a staff research associate at the UC Davis Wildlife Health Center. “It was interesting to see such striking results over a relatively short time period.”

Santa Catalina Island foxes are intensively managed by the Catalina Island Conservancy. In 2009, when the mite treatment study began, the Conservancy added acaracide to the variety of preventative treatments they administer to the foxes each year.

The Conservancy confirms that, in the years since, the overall prevalence of ear mites has dramatically declined in the areas they normally catch and treat foxes, as have the rates of tissue masses in the ear canals, suggesting reduced tumor presence.

“The annual prophylactic acaracide treatment has greatly improved the overall condition of the foxes’ ear canals,” said Julie King, the Conservancy’s director of Conservation and Wildlife Management and co-author of both studies. “Within just a few months post treatment, the presence of wax, infection, inflammation, and pigmentation virtually disappear. We have also noted an apparent reduction in the number of tumors observed, despite the fact that the absence of wax and other obstructions has made them easier to detect.

Conservancy biologists have also documented a cascade effect on the foxes’ offspring, since most young foxes get the ear mites from their parents. “Prior to treatment in 2009, approximately 90 percent of all pups handled had ear mites, whereas by 2015, mites were detected in only 15 percent of new pups.” King said.

The studies pose new questions. For instance, the mite treatment certainly reduces the prevalence and severity of mite infection, as well as risk factors for tumor development, but what effect will it have on overall tumor and cancer rates for these foxes in the long term?

Also, ear mites infect other Channel Island foxes, but those foxes don’t develop ear canal tumors. So why are Santa Catalina Island foxes predisposed to these tumors and not other Channel Island foxes? Vickers and colleagues are preparing to research possible genetic reasons for this.

“Catalina foxes have an over-exuberant tissue reaction to the same stimuli–the mites–and that appears to lead to the tumors,” Vickers said. “That’s why we gravitate toward genetics in addition to other factors.” The Santa Catalina Island fox is one of six subspecies native to the Channel Islands off the coast of Southern California. Its population declined dramatically in 1999 when a distemper epidemic decimated up to 90 percent of the population, prompting the federal endangered species listing for the roughly 150 foxes remaining. The population has since rebounded to an estimated 1,717 foxes.

http://www.sciencedaily.com/   Science Daily

http://www.sciencedaily.com/releases/2015/12/151207151259.htm  Original web page at Science Daily

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Study uncovers hard-to-detect cancer mutations

New research shows that current approaches to genome analysis systematically miss detecting a certain type of complex mutation in cancer patients’ tumors. Further, a significant percentage of these complex mutations are found in well-known cancer genes that could be targeted by existing drugs, potentially expanding the number of cancer patients who may benefit.

The study, from Washington University School of Medicine in St. Louis, appeared Dec. 14 in the journal Nature Medicine.

“The idea of not catching a targetable mutation in a patient’s tumor is devastating,” said senior author Li Ding, PhD, associate professor of medicine and assistant director of the McDonnell Genome Institute at Washington University. “We developed a software tool for finding a certain type of genetic error that has been consistently missed by cancer genome studies. We identified a large number of such events in critical cancer genes. The ability to discover such events is crucial for cancer research and for clinical practice.”

Mutations in the genome happen in a variety of ways. Perhaps the simplest is a change in a single “letter” of the DNA code. Among the more complex types of mutations are those that involve deleting or inserting a few letters. In the new study of 8,000 cancer cases, the investigators focused on mutations involving letters that are inserted at the same time that other letters are deleted.

“We call this type of mutation a complex indel because insertion and deletion is happening at the same time, in the same genomic location,” Ding said. “It is very difficult to capture such events because conventional approaches were designed to catch one or the other, not both types at the same time and place.”

To find the complex indels, the researchers developed specialized computer software and verified its accuracy in genome sequences into which they purposely introduced these complex mutations.

Then, the researchers looked at cancer genomes that already had been sequenced and found 285 complex indels in genes known to be associated with cancer. About 81 percent of these complex indel events had been missed on the first analysis using conventional approaches. And another 18 percent had been misidentified as some other type of mutation.

Ding emphasized the importance of developing special tools to find these complex indels, as the data suggest they go almost completely undetected by existing tools and appear to cluster in important cancer genes more often than can be attributed to random chance. This information is particularly valuable when indels are found in genes that already have drugs designed to counter the effects of mutation.

In particular, the researchers identified complex indels in the gene EGFR, which is implicated in lung cancer. If such an indel is found in this gene, Ding and her colleagues suggest a patient may benefit from an EFGR inhibitor, such as erlotinib, regardless of the tumor type. The investigators also found complex indels in a gene called KIT, which appears to play a role in melanoma. The analysis suggests that patients with complex indels in KIT would benefit from drugs such as imatinib, sunitnib and sorafenib, which target mutations in this gene.

The new software the investigators developed specifically to find complex indels is called Pindel-C. It was built on top of existing software called Pindel, which was published in 2009 by the study’s first author, Kai Ye, PhD, assistant professor of genetics. Both versions of the software are freely available online for download.

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http://www.sciencedaily.com/releases/2015/12/151214130353.htm  Original web page at Science Daily

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Cancer studies clash over mechanisms of malignicy

The proliferation of blood cells in leukaemia is just one example of unchecked tissue growth associated with cancer — but the extent to which external and internal factors drive this process is open to debate.

Most cases of cancer result from avoidable factors such as toxic chemicals and radiation, contends a study published online in Nature on 16 December (S. Wu et al. Nature http://dx.doi.org/10.1038/nature16166; 2015). The paper attempts to rebut an argument that arose early this year, when a report in Science concluded that differences in inherent cellular processes are the chief reason that some tissues become cancerous more frequently than others (C. Tomasetti and B. Vogelstein Science 347, 78–81; 2015).

The work led to assertions that certain forms of cancer are mainly the result of “bad luck”, and suggested that these types would be relatively resistant to prevention efforts. “There’s no question what’s at stake here,” says John Potter of the Fred Hutchinson Cancer Research Center in Seattle, Washington, who studies causes of cancer. “This informs whether or not we expend energy on prevention.”

In their Science paper, mathematician Cristian Tomasetti and cancer researcher Bert Vogelstein at Johns Hopkins University in Baltimore, Maryland, calculated the relationship between the number of stem-cell divisions and the risk of developing cancer in various tissues. Every instance of cell division comes with a risk that DNA will be incorrectly copied, leading to mutations — some of which could contribute to cancer. The duo’s analysis found a correlation: the more stem-cell divisions that occur in a given tissue over a lifetime, the more likely it is to become cancerous.

Tomasetti and Vogelstein then sorted types of cancer according to how much of the variability in risk is due to stem-cell divisions versus to some ‘extrinsic’ factor, such as environmental exposure to carcinogens. The authors argued that although some cancers clearly had strong environmental links — such as liver cancers caused by hepatitis C infection or lung cancer resulting from smoking — there were others for which the variation was explained mainly by defects in stem-cell division. In those cases, they argued, early detection and treatment would be more effective than prevention.

Something about that did not sit right with Yusuf Hannun, a cancer researcher at Stony Brook University in New York. “What they did was interesting, but I was startled by the conclusion,” he says.

The original work, Hannun and his colleagues argue, assumed that the two variables — intrinsic stem-cell division rates and extrinsic factors — were entirely independent. But what if environmental exposures affect stem-cell division rates, as radiation is known to do?

Hannun and his team also used other lines of evidence to try to pinpoint the contribution of environmental factors to cancer risk. They looked at epidemiological data showing that, for example, people who migrate from regions of lower cancer risk to those with higher risk soon develop disease at rates consistent with their new homes. The authors also examined patterns in the mutations associated with certain cancers; ultraviolet light, for example, tends to create a tell-tale signature of mutations in DNA. And they used other mathematical models, expanding the data set used in the earlier work to include prostate and breast cancer — two of the most common cancers. “There’s no question what’s at stake. This informs whether or not we expend energy on prevention.”

The models suggested that mutations during cell division rarely build up to the point of producing cancer, even in tissues with relatively high rates of cell division. In almost all cases, the team found that some exposure to carcinogens or other environmental factors would be needed to trigger disease.

Tomasetti counters that he never intended to explain why cancers develop. His analysis, he says, was based on normal stem-cell division in healthy tissue and was meant to explain only why some cancers are more prevalent than others. He also argues that the models created by Hannun and his colleagues make too many assumptions and fail to incorporate some features of tumour growth.

Some specialists in cancer prevention welcome the Nature paper because of fears that the public — and possibly also funders of scientific research — might conclude that prevention efforts are not worthwhile, says Edward Giovannucci, who studies cancer prevention at the Harvard T. H. Chan School of Public Health in Boston, Massachusetts. “By not smoking, your lifetime risk of lung adenocarcinoma drops dramatically,” he says. “The fact that your risk of pelvic sarcoma is even lower because there’s less stem-cell division — so what?”

Nature 528, 317 (17 December 2015) doi:10.1038/528317a

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/cancer-studies-clash-over-mechanisms-of-malignancy-1.19026  Original web page at Nature

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Tumor network in brain increases treatment resistance

Astrocytomas are special type of brain tumours that are difficult to treat, because they do not respond to standard forms of treatment. One reason for this resistance could be their ability to form a communication network. This was discovered by scientists taking part in an international study involving experts from the Comprehensive Cancer Center (CCC) of MedUni Vienna and Vienna General Hospital. The study has now been published in the journal Nature and is regarded as a milestone by the medical world.

Gliomas are tumours of the central nervous system (brain tumours) and are subdivided into astrocytomas and oligodendrogliomas. Whilst oligodendrogliomas are relatively rare, with only 40 new cases every year, and respond well to standard radiotherapy and chemotherapy treatments, astrocytomas are highly invasive and difficult to treat. For this reason they are also associated with a poor prognosis: sufferers usually only survive for a few years. In Austria around 400 people develop an astrocytoma every year.

Until now it has not been understood why astrocytomas respond so poorly to current treatments compared with other gliomas. In the present study, which was set up in collaboration with the University of Heidelberg, the study team successfully identified a starting point that opens up the possibility of treating astrocytomas more effectively in future. Matthias Preusser, specialist in brain tumours at the University Department of Internal Medicine I at MedUni Vienna and Vienna General Hospital, head of the CCC unit for tumours of the central nervous system (CCC-CNS) and co-author of the new study, in which the Clinical Institute for Neurology of MedUni Vienna and Vienna General Hospital also took part, says: “Astrocytomas form interconnecting communication networks. To do this, the tumour cells form long thin channels from their membranes, so-called tumour microtubules, that connect them to other tumour cells. They use these channels to exchange information and molecules in the form of electrical charges and calcium. This network favours the spread of tumour cells, cell division and makes astrocytomas more resistant to treatment.” Indeed, using this network, astrocytomas are able to initiate repair mechanisms and so eliminate any damage to individual tumour cells caused, for example, by radiotherapy treatment.

One approach to achieving more therapeutic success in the future is to disrupt communication between the astrocytomas by blocking the channel system. Preusser: “It is conceivable that greater therapeutic success could be achieved by using drugs to disrupt the formation or function of the membrane channels.” The research team was able to show that the network interfaces are created by a certain molecule, connexin 43, that is able to form pores. On the other hand, the protein GAP 43 seems to play an important role in the formation of the microtubules. Preusser: “Potential treatment strategies could therefore be to chemically inhibit the tumour cell network using calcium blockers or substances that affect connexin 43 or GAP 43.”

http://www.sciencedaily.com/  Science Daily

http://www.sciencedaily.com/releases/2015/11/151105092002.htm  Original web page at Science Daily