New drug limits cancer spreading

A research team that recently invented a drug to stop blood vessels from forming a treatment-resistant barrier around some cancers has now discovered the drug can be used to prevent cancer from spreading.

"We originally developed the drug to overcome a problem in some cancers that grow a chaotic barrier of blood vessels in the tumor which prevents the body's immune cells and treatments like chemotherapy entering the tumor," said Professor Ruth Ganss Co-Head of the Cancer and Cell Biology Division at Perth's Harry Perkins Institute of Medical Research.

"The drug also sets-up lymph-node-like structures within the cancer to draw in a patient's immune system and greatly enhance a patient's own capacity to shrink the cancer.

"What we've since discovered is that by 'normalizing' blood vessels the drug also stops cancer spreading because it counteracts the cancer's influence on blood vessels in other parts of the body.

"Cancer spreads when cancer cells travel through the blood stream and settle and grow in other organs, like the lung or brain.

 "They are able to establish themselves in a distant body part because the primary tumor secretes substances that make blood vessels in other organs 'leaky,' or easier to penetrate.

"So when cancer cells travel in the blood stream they typically settle and grow where there are optimal conditions that have actually been created by the primary tumor.

"The primary tumor effectively 'talks' to the site where the metastasis is going to form so when the floating cancer cells arrive, they find a nice cozy environment in which to grow.

"While this behavior of cancer was already known, what we have discovered is that we can interfere with this process because of the way this new drug affects blood vessels.

"We've discovered it restores the leaky vessels which result in the cancer cells flowing past and not setting up shop.

"For a patient, this means that in future it will be possible to remove the primary tumor, then use the new drug to prevent cancer cells in the blood system from successfully attaching themselves to another organ and growing.

"But, if the cancer cells have already settled elsewhere and started growing then the drug can also be used to increase the number of immune cells brought into the new tumor to help it shrink."

"So we now have a drug that not only opens up the primary tumor for increased immunotherapy and greater treatment access, but it prevents metastatic spreading and if cancer has already spread, then the drug escalates the patient's immune response to new cancer.

"We now know we can interfere early and late in cancer's journey," Professor Ganss said.

Co-author of the publication, Dr. Bo He who undertook laboratory work on the drug said the research focused on metastatic cancer because most patients succumb to secondary cancers, not the primary.

"Using the drug that the team developed and published in 2017 in Nature Immunology we explored whether it could prevent metastases as well as improve patient immune response."

"We're quite excited that we have moved into a different phase of exploring how this drug could be used.

"So far we've successfully applied it to melanoma and lung cancer models in a metastatic setting," said Dr.

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New drug reduces symptoms of Rett syndrome in preclinical models

A new article published in the Cell Reports describes how a new drug is able to reduce the symptoms and activate the dormant neurons characteristic of Rett Syndrome in preclinical models. The study, led by Dr. Manel Esteller, Director of the Epigenetics and Cancer Biology Program (PEBC) of the Bellvitge Biomedical Research Institute (IDIBELL), ICREA Researcher and Professor of Genetics of the University of Barcelona, and Dr. Sonia Guil, researcher at the same IDIBELL group, has been possible thanks to the support from the Catalan and Spanish associations of the Rett Syndrome, the Carla Regatta, a Verkami crowfunding campaign, the Jérôme Leujene Foundation and the Dischrom project funded by EU.

Rett Syndrome is the second most frequent cause of intellectual disability in women, only after Down Syndrome. The main genetic cause of Rett Syndrome is the appearance of mutations in the embryo affecting the MECP2 gene, a regulator of the expression of other genes in the genome. There is no specific pharmacological treatment for the disease, so current efforts are focused on trying to control its most serious manifestations, such as epileptic and respiratory crises.

"We knew for some years that the brains of Rett syndrome girls were inflamed, so we decided to test whether a drug that inhibits a central neuroinflammatory protein called glycogen synthase kinase-3B (GSK3B) could reverse part of the symptoms. As with any experimental treatment, we started with a preclinical model of the disease, studying it in mice that have the same MECP2 deficiency as in human Rett syndrome" says Dr. Manel Esteller.

"The results have been very promising; agent SB216763 has been able to lengthen the life of the animals, significantly reducing tremors, breathing difficulties and mobility limitations. But what is really remarkable is that the inhibition of GSK3B also causes an "awakening" of the sleeping neurons of the syndrome: these brain cells are now beginning to regain contact between them and communication between neuronal synapses increases", explains the IDIBELL researcher, and he concludes: "Our findings provide a new way of improving the quality of life of these patients and now it is the neurologists' job to demonstrate their applicability in patients with Rett Syndrome. In any case, we have to be aware that the mutation in the MECP2 gene is still there, and only by correcting it would we arrive at a definitive treatment of the disease."

Ref : http://www.idibell.cat/modul/news/en/1076/a-new-drug-shows-preclinical-efficacy-in-rett-syndrome

New drug treatment could reduce body weight in obese patients with rare genetic disorder

As part of a phase II study at Charité - Universitätsmedizin Berlin and the Berlin Institute of Health, two obese patients with a rare genetic disorder were given a drug treatment to stimulate the satiety center in the brain. After only a few weeks, both patients, which were severely hyperphagic before the study start, showed a normalization of their hunger feeling as well as a significant reduction of body weight. Results from this study have been published in the current edition of the New England Journal of Medicine.

Our understanding of the factors involved in the dysregulation of normal body weight remains rudimentary. However it is known that mutations in certain genes play could lead to the development of early onset obesity due to a severe hyperphagia. MC4R is one example; it provides the blueprint for the melanocortin-4 receptor (MC4R) setmelanotide, which regulates energy balance and weight. Activation of the receptor by MSH (melanocyte-stimulating hormone) leads to a reduction in the sensation of hunger. Patients deficient in MSH show severe hyperphagia, and develop obesity within the first months of life.

The study team, led by Dr. Peter Kühnen - a physician at the Institute for Experimental Pediatric Endocrinology -- treated two patients with congenital proopiomelanocortin (POMC) deficiency. POMC is a precursor of the hormone MSH, and is secreted by the hypothalamus; deficiency causes significantly increased hunger. The researchers set out to test whether the new drug might replace the effect of the prohormone through targeted activation of the satiety center. First effects were recorded within a few weeks of the start of treatment. Patient 1, whose starting weight was 155 kg, achieved a total weight loss of 51 kg over a period of 42 weeks; patient 2 (starting weight 152.8 kg) lost a total of 20.5 kg over the course of 12 weeks.

"Our study results confirm the crucial role of the MC4R signaling pathway in appetite regulation, and represent an important contribution to our understanding of the fundamental processes involved in the control of body weight" says Dr. Peter Kühnen. He goes on to add: "It currently remains unclear, however, whether this treatment will be of benefit to patients whose obesity has no clear genetic cause. Further studies will be needed to elucidate this."

Ref : http://www.nejm.org/doi/full/10.1056/NEJMoa1512693

New drug that combines methicillin with polymer BPEI can combat MRSA

A University of Oklahoma team of chemists has developed a new antibiotic formulation to fight the sometimes deadly staph infection  caused by methicillin-resistant  S. aureus or MRSA and other antibiotic-resistant infectious bacteria. The new drug to treat MRSA combines traditional Food and Drug Administration-approved antibiotics, such as methicillin, with the polymer BPEI.

Charles Rice, principal investigator and professor in the Department of Chemistry and Biochemistry, OU College of Arts and Sciences, with team members Robert Cichewicz and Daniel Glatzhofer, both OU chemistry professors, has been able to invigorate older drugs from the penicillin family by combining them with BPEI. While this new formulation requires FDA approval, the approach restores efficacy to obsolete antibiotics.

"The use of first-line antibiotics to kill MRSA or other infectious bacteria will improve patient outcomes and lower the economic burden,"  Rice said. "The discovery in our laboratory has made it possible to create an effective antibiotic that can reduce expensive hospitalization costs."

Leading up to the discovery, Rice was working in his laboratory when he discovered a way to neutralize the MRSA bacteria so that it is no longer resistant to methicillin. This method can be used to neutralize other infectious bacteria. The takeaway from these experiments is that any number of penicillin-type drugs combined with BPEI or related polymers could create a new first-line drug for treating infectious diseases and change how MRSA and other infectious bacteria are treated.

The Centers for Disease Control considers MRSA a serious threat to human health. MRSA infected 80,500 people in 2011 and nearly one in seven cases resulted in death. When MRSA colonies invade host tissue, they release toxins that cause tissue injury leading to patient morbidity. Until now, more costly and highly toxic antibiotics of last resort were used to treat MRSA. The new first-line combo drug developed at OU by Rice and his team has the potential to change how patients with MRSA are treated.

Ref : https://ou.edu/content/publicaffairs/archives/OUTeamDevelopsNewAntibioticFormulationtoFightMRSAandOtherAntibioticResistantBacteria.html

New drug shows promise against Huntington's disease

A drug that would be the first to target the cause of Huntington's disease (HD) is effective and safe when tested in mice and monkeys, according to data released today that will be presented at the American Academy of Neurology's 68th Annual Meeting in Vancouver, Canada, April 15 to 21, 2016. A study to test the drug in humans has begun.

Huntington's disease is a rare, hereditary disease that causes uncontrolled movements, loss of intellectual abilities, emotional problems and eventually death. The disease is passed from parent to child through a mutation in the huntingtin gene. The mutation results in the production of a disease-causing huntingtin protein. Each child has a 50/50 chance of inheriting the gene mutation. Everyone who inherits the mutated gene will eventually develop the disease.

The new drug, called IONIS-HTTRx, is an antisense drug that acts as a "gene silencer" to inhibit the production of huntingtin protein in people with Huntington's disease.

"It is very exciting to have the possibility of a treatment that could alter the course of this devastating disease," said clinical study principal investigator Blair R. Leavitt, MD, of the University of British Columbia in Vancouver. "Right now we only have treatments that work on the symptoms of the disease." Leavitt notes the drug is still years away from being used in human clinical practice.

Earlier studies in mouse models of Huntington's disease showed that treatment with antisense drugs delays disease progression and results in sustained reversal of the disease phenotype. In YAC128 mice, a transgenic model of HD, motor deficits improved within one month of initiating antisense treatment and were restored to normal at two months after treatment termination. Motor skills of antisense-treated BACHD mice, another transgenic model of HD, improved eight weeks after initiation of treatment and persisted for at least nine months after treatment termination. In monkeys, dose-dependent reductions in HTT mRNA and Htt protein throughout the central nervous system were observed after intrathecal administration of an antisense drug. Reduction of cortical huntingtin levels by 50 percent was readily achieved in monkeys and correlated with 15 to 20 percent reduction in the caudate. In further tests in rodents and monkeys, IONIS-HTTRx was found to be well-tolerated without any dose-limiting side effects.

New drug shows promise against Huntington's disease

Potential new painkiller provides longer lasting effects ..........

Medications have long been used to treat pain caused by injury or chronic conditions. Unfortunately, most are short-term fixes or cause side effects that limit their use. Researchers at the University of Missouri have discovered a new compound that offers longer lasting painkilling effects, and shows promise as an alternative to current anesthetics.

"Because of its versatility and effectiveness at quickly numbing pain in targeted areas, lidocaine has been the gold standard in local anesthetics for more than 50 years," said George Kracke, Ph.D., associate professor of anesthesiology and perioperative medicine at the MU School of Medicine and lead author of the study. "While lidocaine is effective as a short-term painkiller, its effects wear off quickly. We developed a new compound that can quickly provide longer lasting relief. This type of painkiller could be beneficial in treating sports injuries or in joint replacement procedures."

Painkillers work by interfering with the nervous system's transmission of nerve signals that the body perceives as pain. Lidocaine is used as an injectable pain reliever in minor surgical or dental procedures, or as a topical ointment or spray to relieve itching, burning and pain from shingles, sunburns, jellyfish stings and insect bites. The new compound developed at MU, boronicaine, could potentially serve many of those same functions as an injectable or topical painkiller.

National Academy of Sciences member M. Frederick Hawthorne, Ph.D., director of MU's International Institute of Nano and Molecular Medicine and a pioneer in the field of boron chemistry, synthesized boronicaine as a derivative of lidocaine. By changing aspects of the chemical structure of lidocaine, the researchers found that the new compound provided pain relief that lasted five times longer than lidocaine. In pre-clinical, early stage studies, boronicaine provided about 25 minutes of relief, compared to about five minutes of pain relief with lidocaine.

"Although some conditions may warrant the use of a short-lasting painkiller, in many cases a longer lasting anesthetic is a better option," Kracke said. "Having a longer lasting anesthetic reduces the dosage or number of doses needed, limiting the potential for adverse side effects." While other types of painkillers can provide longer pain relief than lidocaine, they can cause heart toxicity, gastrointestinal issues and other side effects. Preliminary findings show no toxicity in single-dose studies of boronicaine, though more studies are needed.

"Boronicaine could have distinct advantages over existing painkilling medications," said Hawthorne, who also serves as the Curators' Distinguished Professor of Chemistry and Radiology at MU. "We're conducting more research into the side effects of the compound, but in time it could very well become a useful material to use as an anesthetic."

Ref : http://onlinelibrary.wiley.com/doi/10.1002/cmdc.201402369/pdf

Potential new painkiller provides longer lasting effects