STUDY IDENTIFIES NEW NUTRIENT-BASED MECHANISM OF CANCER PROLIFERATION, DRUG RESISTANCE.

Cancer researchers have known for years that tumours have unusual metabolisms, their rapid use of glucose is used as a diagnostic tool for tumours in PET scans.  However, only recently have scientists begun to flesh out the details of this metabolic shift.  Now, a new study from researchers at the Ludwig Cancer Research and University of California, San Diego have shown that glioblastoma tumours can leverage glucose and another nutrient, acetate, to resist targeted therapies directed at specific cellular molecules.

The team state that the findings, demonstrate that nutrients can strongly affect the signaling molecules that drive tumours.  They go on to add that the current study shows that metabolic and nutritional factors might be quite important in cancer development and treatment. The new study also highlights one way that glioblastoma tumours can evade targeted drugs such as erlotinib and gefitinib, inhibitors of a mutant form of the cellular molecule EGFR (epidermal growth factor receptor) that drives the growth of many glioblastomas and other tumour types.  The opensource study is published in the journal Proceedings of the National Academy of Sciences.

Previous studies from the team as well as other groups show that this shift can occur through the activation of a central cellular signal, mTORC2 (mTOR complex 2). mTORC2 is involved in switching cancer cells to a hyperactive metabolic state, for instance prompting the increased influx of glucose and acetate into cancer cells. Glucose and acetate provide fuel and cellular building blocks to perpetuate the rapid growth of tumours.

The current study found that glucose and acetate in turn regulate mTORC2, propelling glioblastoma tumour growth and fending off targeted drugs.  The team explain that this is a two way street as signaling molecules like mTORC2 can change metabolism, and metabolites can change mTORC2.

The findings first emerged from experiments in glioblastoma cells cultivated in a petri dish. In one experiment, the researchers treated the cells with either glucose or acetate and found that at least one of these nutrients was required in order to turn on mTORC2 in response.

The researchers also tested glioblastoma cells with a mutant form of EGFR that turns on mTORC2 and propels  tumour growth. In the absence of glucose and acetate, EGFR inhibitors can switch off mTORC2 signaling. However, when the researchers added glucose and acetate, the drugs did not work, mTORC2 stayed on and the cells thrived. The researchers delved further, showing how acetate and glucose activate mTORC2 through a molecule formed from these metabolites, called acetyl-coA, which is critical for activating a key component of mTORC2.

The results show that glucose or acetate can activate mTORC2 through the production of acetyl-coA, enabling tumours to resist targeted therapies such as EGFR inhibitors. Activated mTORC2 in turn propels tumour growth by regulating metabolism and other cellular processes. The researchers provide evidence that a similar mechanism operates in cells taken directly from glioblastoma patients and in human glioblastoma cells implanted into mice.

The data findings provide a window into the treatment of glioblastoma, which leaves most newly diagnosed patients with less than two years to live. To reduce deadly brain swelling, many glioblastoma patients require treatment with steroids, which are known to raise blood glucose levels. The current study suggests that the drugs, which may be necessary to control brain swelling, could also have the paradoxical effect of propelling tumour growth through activation of mTORC2. The results also suggest that developing drugs to effectively target mTORC2 may be one avenue to shutting down glioblastoma and possibly other types of tumours.

The researchers hypothesize that this may be a general mechanism in cancer and are now planning to investigate the role of glucose and acetate in other types of tumours.  The team also theorise about how to modify diet in mice to affect the production of these and other metabolites.

The lab note that the study does not point to the value of any particular diet for counteracting cancer and state that it is going to take diligent and careful work to determine how lifestyle changes, including diet, can alter tumour cell metabolism. They are actively studying this process and hope that this information can be used to develop more effective prevention and treatment strategies for cancer patients.

The team conclude that the current study suggests that there may be more interplay between genes involved in cancer and the environment than previously thought.

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Source:  Ludwig Cancer Research

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DECADES OLD MYSTERY SOLVED AS RESEARCHERS MAP THE EFFECT OF T2 DIABETES ON THE LYMPHATIC VESSELS.

Approximately 28 million Americans live with Type 2 diabetes, a condition characterized by high blood sugar levels.  The immune system plays a part in type 2 diabetes. Researchers have linked insulin resistance to high levels of cytokines, which are released in response to inflammation in the body.  The immune system’s response to inflammation leads to fat cells being unable to respond well to insulin and sees the fat cells releasing fatty acids into the blood, leading to higher than normal levels of cholesterol.  It has long been known that if the patient has diabetes, is at risk of diabetes, or has a family history of diabetes one of the first symptoms to show is enlargement of lymph nodes, the lymphatic system is a major part of the immune system.

However, there is still much that is unknown as to how diabetes effects the body’s lymphatic vessels. Now, a study from University of Missouri researchers has identified for the first time how the condition affects lymphatic vessels, a breakthrough that could lay the groundwork for new therapies to improve the lives of people with Type 2 diabetes.  The opensource study is published in the journal Cardiovascular Research.

Previous studies show that the lymphatic system’s primary role is to transport lymph, a clear fluid that contains white blood cells that help rid the body of antigens, to lymph nodes where immune responses are activated. The current study shows for the first time that when individuals have Type 2 diabetes, the walls of their lymphatic vessels are defective and become increasingly permeable, or leaky.

The team likens the permeability of a healthy lymphatic vessel to a porous garden hose, which is designed to allow water to escape through small holes in the hose. However, they explain that a lymphatic vessel in a person with Type 2 diabetes is like a porous garden hose that has been drilled with large holes, letting too much water escape. The results show that when the lymphatic vessel is too permeable, lymph and antigens are not transported to the lymph nodes.

Studying lymphatic vessel function in animals has been a challenge for researchers, because unlike blood vessels, lymph vessels are clear and appear almost invisible. However, the researchers developed a new investigative method to measure lymphatic vessel permeability and found that the vessels in Type 2 diabetes produced nitric oxide levels much lower than healthy lymphatic vessels.

The results showed that when an individual has Type 2 diabetes, cells in the lymphatic vessels aren’t producing enough nitric oxide, which is essential to maintaining the integrity of their endothelial layer so that they function properly. The researchers found that by giving the lymphatic vessels L-arginine, an amino acid commonly found in red meat, poultry, dairy products and nutritional supplements, they were able to boost their nitric oxide production and restore their ability to act as a barrier.

While more studies are needed, the lab  is hopeful the findings could lead to further research for developing new treatments or therapies for individuals with Type 2 diabetes.

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RESEARCHERS HAVE VISUALISED CHANGES MADE TO RNA IN THE BRAIN BY ADMINISTERED DRUGS.

A group of researchers from Kyoto University have successfully visualized RNA behaviour and its response to drugs within the living tissue brain of live mice by labeling specific RNA molecules with fluorescent probes. The team state that their study can potentially lead to faster, and more accurate screening processes for the discovery and development of new drugs.  The opensource study is published in the journal Nucleic Acids Research.

Previous studies show that RNA is a molecule that plays a key role within a living organism, holding information as to when, where and how much protein must be allocated, which is also responsible for controlling the biological reactions within a living cell. RNAs behave uniquely and are distributed unequally in each cell, existing more in some areas of the cell than others depending on environmental factors and cell conditions. In some cases, these chemical changes can put the cell’s health at risk due to RNA disruption. However, it is unclear as to how the distribution of RNA molecules is regulated in the cell, and what causes them to act abnormally.

The current study introduced fluorescent probe within the brain of live mice, the team succeeded in visualizing targeted RNA in the cell nucleus. The researchers explain that this fluorescent probe emits varying intensities of light depending on RNA concentration levels enabling them to effectively quantitatively analyze RNA in the living body. The data findings show that the imaging technique quantitatively conveyed that the RNA behaviour in live tissue differed from that of a cultured cell when a drug was administered.

The team hope that this new imaging technique can help reveal the natural state of RNA and allows them to observe the emergence and disappearance of RNA clusters in many types of species, including those that cannot be genetically engineered.  The researchers next goal is to investigate differences of RNA activity in a live, single cell, and what regulates RNA activity.  They also plan to compare healthy and unhealthy tissue to elucidate gene expression mechanisms caused by abnormal RNA activity.

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Source:  Kyoto University’s Institute for Integrated Cell-Material Sciences (iCeMS)

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Engineered particles ‘may become antibiotics of the future’

There is a pressing need for new approaches to fight harmful bacteria as the global threat of rising drug resistance appears set to outpace the rate at which we can produce new antibiotics to fight deadly infections like tuberculosis.

Now, researchers in the field of synthetic biology have addressed this challenge in a different way. They have engineered particles called “phagemids” that enter targeted harmful bacteria and release toxins that kill them.Writing in the journal Nano Letters, the team, led by researchers from the Massachusetts Institute of Technology (MIT) in Cambridge, describe how they modeled their particles on bacteriophages – viruses that infect and kill bacteria.Unlike broad-spectrum antibiotics, bacteriophages target specific bacteria while leaving friendly bacteria intact. They have been used for many years in various countries – for instance, in those that were in the former Soviet Union.But the disadvantage of treatments that use bacteriophages is they can have harmful side effects, as lead investigator James Collins, an MIT professor of medical engineering, explains:

“Bacteriophages kill bacteria by lysing the cell, or causing it to burst. But this is problematic, as it can lead to the release of nasty toxins from the cell.”

The toxins that are released when the harmful bacteria burst can cause sepsis, and even death in some cases, he adds. Sepsis is where the infection causes the immune system to go into overdrive, triggering widespread inflammation, swelling and blood clotting.

Phagemids infect targeted bacteria with engineered plasmids

In previous work, the team had already engineered bacteriophages that released proteins that boosted the effectiveness of antibiotics without bursting the bacterial cells.For the new study, the researchers developed a particle that works in a similar way – it targets and kills specific bacteria, without causing the cells to burst and release their toxins.They call the particles “phagemids” because they infect the target bacteria with plasmids – small DNA molecules that can copy themselves inside cells.Using synthetic biology, the team engineered the plasmids to express proteins and peptides – short-chain amino acids – that are toxic to the bacterial host cell. The toxins are designed to disrupt key cell processes such as replication, with the effect that the bacterial cell dies without bursting.

The team systematically tested a variety of peptides and toxins and showed how, when some are combined in the phagemids, they kill the great majority of bacterial cells within a culture.

The method they have developed is highly targeted – it attacks only specific species of bacteria, which means you can use it to treat an infection without harming the rest of the microbiome, Prof. Collins explains.

Resistance likely to develop more slowly

The researchers say exposure to the phagemids did not appear to cause the bacteria to develop any significant resistance, suggesting several rounds of phagemids could be delivered to get a more effective treatment.Prof. Collins says he expects the bacteria will eventually become resistant, but probably much more slowly than they would after repeated use of bacteriophages.He sees the phagemids being used alongside rapid diagnostic tools, currently in development, that would allow doctors to treat specific infections, and explains:

“You would first run a fast diagnostic test to identify the bacteria your patient has, and then give the appropriate phagemid to kill off the pathogen.”

The team has experimented with phagemids designed to kill Escherichia coli and now plans to develop a broader range that can kill pathogens like Clostridium difficile and Vibrio cholerea – the bacterium that causes cholera.Alfonso Jaramillo, a professor of synthetic biology at the University of Warwick in the UK – who was not involved in the research – says the researchers have created an improved phage therapy that may become the antibiotics of the future.

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Experimental drug that may repair nerve damage in MS moves forward

A new study suggests that an investigational drug for multiple sclerosis (MS) may repair myelin according to a study that will be presented at the American Academy of Neurology’s 67th Annual Meeting in Washington, DC, April 18 to 25, 2015.

“This study, for the first time, provides biological evidence of repair of damaged myelin in the human brain, and advances the field of neuro-reparative therapies,” said study lead author Diego Cadavid, MD, with Biogen in Cambridge, Mass., and a fellow with the American Academy of Neurology.

The Phase 2 study involved 82 people who had their first incident of acute optic neuritis, a disease that typically affects one eye and is characterized by inflammation, damage to the nerve fibers and loss of myelin within the optic nerve. It is estimated that about half of people with optic neuritis will later develop multiple sclerosis.

All participants were treated with high dose steroids and then randomly selected with equal probability to receive either the experimental antibody, called anti-LINGO-1, or a placebo once every four weeks, for a total of six doses. Participants were then assessed every four weeks for six months and a final visit at eight months. The drug’s effectiveness in repairing myelin was evaluated by comparing the recovery of the optic nerve latency in the damaged eye at six and eight months to the normal unaffected eye at the start of the study.

The main finding of the study focused on the latency of the visual evoked potential (VEP), a test that measures the visual system’s ability to conduct electrical signals between the retina and the brain. The results showed that people treated with the experimental drug and who did not miss more than one dose (per protocol population) had significantly improved conduction as measured by latency recovery compared to people who received the placebo. At six months, those who received the drug improved on average by 7.55 milliseconds, or 34 percent, compared to placebo. The effect continued to eight months with an average improvement of 9.13 milliseconds or 41 percent over placebo.

In addition, the percentage of subjects whose VEP latency in the affected eye recovered to normal or nearly normal (within 10 percent of the normal eye) more than doubled, from 26 percent on placebo to 53 percent on the drug.A substudy using an exploratory method of measuring latency called multifocal VEP revealed similar treatment effects.“More studies are needed to evaluate whether these changes lead to clinical improvement,” said Cadavid.A second study of anti-LINGO-1 in people with multiple sclerosis is ongoing.

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Cancer patients treated in world-first clinical trial of Canadian viral therapy

Canadian researchers have launched the world’s first clinical trial of a novel investigational therapy that uses a combination of two viruses to attack and kill cancer cells, and stimulate an anti-cancer immune response. Previous research by this team and others worldwide suggests that this approach could be very powerful, and could have fewer side effects than conventional chemotherapy and radiation, although it will take years to rigorously test through this trial and others.

The therapy was jointly discovered and is being developed by Dr. David Stojdl (Children’s Hospital of Eastern Ontario, University of Ottawa), Dr. Brian Lichty (McMaster University) and Dr. John Bell (The Ottawa Hospital,University of Ottawa), and their respective research teams and colleagues. The clinical trial, which is funded by the Ontario Institute for Cancer Research and coordinated by the NCIC Clinical Trials Group, is expected to enroll up to 79 patients at four hospitals across Canada. Up to 24 patients will receive one of the viruses and the rest will receive both, two weeks apart.

Christina Monker, 75, a former nurse from Rockland, Ontario, is one of the first patients treated in the trial. She was diagnosed with cancer in 2012 and, despite six weeks of radiation therapy and two rounds of chemotherapy, the cancer spread to both her lungs. After completing another 30 rounds of chemotherapy, she enrolled in the trial at The Ottawa Hospital and was treated on June 2, 2015.

“The nausea of chemotherapy was worse than I ever could have imagined, but with the viral therapy I just felt like I had the flu for a couple of days, and the symptoms were easily managed,” said Ms. Monker. “It is too soon to know if I may have benefited from this therapy, but I’m very glad to contribute to this important research that could improve care for others.”

The idea of using viruses to treat cancer has been around for more than a century, with sporadic reports of cancer patients experiencing remarkable recoveries after viral infections. However, it is only in recent years that viral therapy has begun to be developed and tested in a rigorous way. Drs. Bell, Lichty and Stojdl began investigating viral therapies for cancer nearly 15 years ago when they worked together at The Ottawa Hospital.

“We found that when normal cells become cancerous, it’s like they are making a deal with the devil,” explained Dr. Bell, a senior scientist at The Ottawa Hospital and professor at theUniversity of Ottawa. “They acquire genetic mutations that allow them to grow very quickly, but these same mutations also make them more susceptible to viruses.”

The two viruses being tested in this clinical trial are called MG1MA3 and AdMA3. MG1MA3 is derived from a virus called Maraba, which was first isolated from Brazilian sandflies, while AdMA3 is derived from a common cold virus called Adenovirus. Both of these viruses have been engineered to stimulate an immune response against cancer cells that express a protein called MAGE-A3, but the Maraba virus also achieves an extra layer of anti-cancer activity by replicating inside many kinds of cancer cells and killing them directly. These viruses are manufactured in specialized facilities at The Ottawa Hospital and McMaster University.

“The idea behind this trial is to use the Adenovirus to prime the patient’s immune system to recognize their cancer, and then use the Maraba virus to directly kill their cancer and further stimulate their immune system to prevent the cancer coming back,” said Dr. Brian Lichty, associate professor at McMaster University. “We’re enthusiastic about the potential of this unique therapy.”

“We’re very excited about this first clinical trial,” said Dr. Stojdl, senior scientist at the Children’s Hospital of Eastern Ontario and associate professor at the University of Ottawa. “We’re continuing to push very hard to develop a suite of biological therapies with the goal of launching similar trials tailored to other types of tumours, including brain cancer and several devastating childhood cancers.”

Viral therapies are one component of a growing field of cancer research that seeks to use biological materials (including cells, genes, antibodies and viruses) to attack cancer cells and stimulate an anti-cancer immune response. This field of research has been called biotherapy or immunotherapy. Dr. Bell and his colleagues recently launched the$60M BioCanRx network to advance this area of research.

The Maraba virus is an important part of a broad biotherapeutics clinical trial development program in Canada that is combining viruses and vaccines with standard and emerging therapies to treat different types of tumours. Drs. Lichty, Bell and Stojdl and their institutions, in cooperation with the Fight Against Cancer Innovation Trust, have formed Turnstone Biologics in order to engage the private sector and to help fund further clinical trials.

“Immunotherapy is a very exciting field of cancer research, with antibody-based therapies showing the most promise in clinical trials so far,” said Dr. Derek Jonker, the overall lead for the clinical trial, a medical oncologist at The Ottawa Hospital and a professor at the University of Ottawa. “Viral therapies have also shown promise in laboratory studies, but it is too soon to know what impact they may have on patients. This clinical trial will help us find out and we’re very grateful to the patients who have participated.”

“Ontario is pleased to support innovative research through the Ontario Institute for Cancer Research,” said Reza Moridi, Ontario Minister of Research and Innovation. “Our investments have enabled our researchers to be at the forefront of this new therapy. Immunotherapy has the potential to vastly improve the way cancer is treated, and is another example of how research investment brings tangible benefits to Ontarians and people around the world.”

“The NCIC Clinical Trials Group is very pleased to conduct this trial, which offers a potential new therapeutic approach for cancer patients that has been developed by Canadian researchers,” said Dr. Janet Dancey, director, NCIC Clinical Trials Group and professor at Queen’s University in Kingston.

“Our Government is committed to investing in research that will accelerate efforts to find a cure for cancer, a disease that kills thousands of Canadians each year. The clinical trial announced today represents an innovative approach to treating cancer. We are proud to have contributed to the development of this therapy and wish the researchers and clinicians every success as they carry out this important study,” said the Honourable Rona Ambrose, Canada’sMinister of Health.

In addition to The Ottawa Hospital, the clinical trial is also taking place at the Juravinski Cancer Centre of Hamilton Health Sciences (under the leadership of Dr. Sebastien Hotte), Princess Margaret Cancer Centre of the University Health Network in Toronto (under the leadership of Dr. Albiruni R A Razak) and the Vancouver Centre of the BC Cancer Agency (under the leadership of Dr. Daniel Renouf). The trial was approved by Health Canada, the Ontario Cancer Research Ethics Board and the BC Cancer Agency Research Ethics Board. Further details about the trial are available at clinicaltrials.gov. Patients wishing to participate in the trial should speak with their own oncologist and ask for a referral to one of the participating hospitals. Further details for patients at The Ottawa Hospital are available online.

While this trial is primarily funded by the Government of Ontario through the Ontario Institute for Cancer Research, many other funding organizations have also supported the research of Drs. Bell, Lichty and Stojdl, including The Ottawa Hospital Foundation, CHEO Foundation, Canadian Cancer Society, Terry Fox Research Institute, Canadian Institutes of Health Research, Ontario Ministry of Research and Innovation, Canada Foundation for Innovation, Ottawa Regional Cancer Foundation, Hair Donation Ottawa, Angels of Hope, BioCanRx, Pancreatic Cancer Canada, NAV Canada and several philanthropic donors.

About the Partners

The Ottawa Hospital is one of Canada’s largest learning and research hospitals with over 1,100 beds, approximately 12,000 staff and an annual budget of over $1.2 billion. Our focus on research and learning helps us develop new and innovative ways to treat patients and improve care. As a multi-campus hospital, affiliated with the University of Ottawa, we deliver specialized care to the Eastern Ontario region, but our techniques and research discoveries are adopted around the world. We engage the community at all levels to support our vision for better patient care.www.ottawahospital.on.ca

McMaster University, one of four Canadian universities listed among the Top 100 universities in the world, is renowned for its innovation in both learning and discovery. It has a student population of 30,000, and more than 170,000 alumni in 137 countries. Its Michael G. DeGroote School of Medicine has a global reputation for educational advancement and its development of evidence-based medicine. McMaster and its academic hospital partner Hamilton Health Sciences are internationally known for their research intensity.

The CHEO Research Institute coordinates the research activities of the Children’s Hospital ofEastern Ontario (CHEO) and is affiliated with the University of Ottawa. Its three programs of research include molecular biomedicine, health information technology, and evidence to practice research. Key themes include cancer, diabetes, obesity, mental health, emergency medicine, musculoskeletal health, electronic health information and privacy, and genetics of rare disease. The CHEO Research Institute makes discoveries today for healthier kids tomorrow. For more information, visit www.cheori.org

The Ontario Institute for Cancer Research (OICR) is an innovative cancer research and development institute dedicated to prevention, early detection, diagnosis and treatment of cancer. The Institute is an independent, not-for-profit corporation, supported by the Government of Ontario. OICR’s research supports more than 1,700 investigators, clinician scientists, research staff and trainees located at its headquarters and in research institutes and academia across the Province of Ontario. OICR has key research efforts underway in small molecules, biologics, stem cells, imaging, genomics, informatics and bio-computing. For more information, please visit the website at www.oicr.on.ca.

The NCIC CTG is the only Canadian cooperative cancer trials group conducting the entire range of cancer trials from early phase studies to large international randomized controlled trials across all cancer types. Its primary mission is to assess the effectiveness of interventions to prevent the development of cancer or improve the care of those patients who do develop cancer. NCIC CTG trials have led to improved outcomes for cancer patients. It is a national research program of the Canadian Cancer Society. The NCIC CTG’s Central Operations and Statistics Office is located at Queen’s University in Kingston, Ontario, Canada

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