Liraglutide drug makes highly desirable foods less appealing to people

In continuation of my update on Liraglutide

Understanding the motivations that drive humans to eat is an important consideration in the development of weight loss therapies. Now a study led by researchers at Beth Israel Deaconess Medical Center (BIDMC) helps explain how the diabetes and weight loss drug liraglutide acts on brain receptors to make enticing foods seems less desirable. The findings were recently presented at ENDO 2016, the annual meeting of the Endocrine Society, and will appear in the May issue of the journal Diabetologia.

"We know that everything that controls our body weight and metabolism is integrated by the brain," said senior author Christos S. Mantzoros, MD, Director of the Human Nutrition Unit in the Division of Endocrinology, Diabetes and Metabolism at BIDMC and Professor of Medicine at Harvard Medical School. "This includes both internal stimuli such as hormones and stress, and external stimuli, such as the smell and appearance of enticing foods."

The Mantzoros laboratory has been studying the differences in the brain activity of individuals who are overweight and individuals of normal weight when they are exposed to desirable foods. These differences are quantified through computer-based neurocognitive testing, as well as imaging tests using fMRI (functional magnetic resonance imaging) to observe alterations in the activity of specific brain areas.

In this new work, the researchers examined the glucagon-like peptide (GLP) hormone, which is secreted by the gastrointestinal tract to regulate metabolism. They also examined the drug liraglutide, which is an analog, or mimicker, of the GLP hormone.

Liraglutide prolongs the action of GLP-1 receptors (protein molecules that respond to the GLP hormone's signal) and is known to work through the digestive tract and the pancreas. Previous animal studies had shown that GLP-1 may also act on the brain, but this had not been confirmed in humans.

Liraglutide drug makes highly desirable foods less appealing to people: Understanding the motivations that drive humans to eat is an important consideration in the development of weight loss therapies. Now a study led by researchers at Beth Israel Deaconess Medical Center helps explain how the diabetes and weight loss drug liraglutide acts on brain receptors to make enticing foods seems less desirable.

Investigational drug abaloparatide-SC may help increase bone mineral density in postmenopausal women

 

The investigational drug abaloparatide-SC (subcutaneous) may help increase bone mineral density in postmenopausal women and reduce their risk of fracture, new industry-sponsored research suggests. The results of the subgroup analysis within the ACTIVE clinical trial will be presented Friday, April 1, at ENDO 2016, the annual meeting of the Endocrine Society in Boston.

"Abaloparatide-SC increased bone mineral density and reduced the risk of vertebral and nonvertebral fractures consistently in postmenopausal women with osteoporosis regardless of their baseline patient characteristics, including age, bone mineral density, and whether or not they had prior fractures," said lead study author Felicia Cosman, MD, endocrinologist and osteoporosis specialist at Helen Hayes Hospital in West Haverstraw, New York, and professor of clinical medicine at Columbia University in New York City.

"If approved by the Food and Drug Administration (FDA), abaloparatide-SC may have the potential to reduce the risk of fractures in postmenopausal women with osteoporosis across a broad range of patient characteristics," said Cosman, who is also a consultant to Radius Health, Inc., in Waltham, Massachusetts.

The researchers investigated patients enrolled in the randomized, double-blind, multinational phase 3 ACTIVE trial to evaluate the efficacy and safety of 80 micrograms of abaloparatide-SC in preventing fractures in otherwise healthy, ambulatory, postmenopausal women with osteoporosis. Overall, 2,463 patient between 49 and 86 years of age were randomized to take one of three medications for 18 months: 80 micrograms of abaloparatide-SC, 20 micrograms of subcutaneous teriparatide (an FDA-approved prescription drug known to increase bone density and strength), or placebo.

Investigational drug abaloparatide-SC may help increase bone mineral density in postmenopausal women

Evolocumab could be more effective than ezetimibe in lowering cholesterol in statin-intolerant patients

 

Ezetimibe                                                                                                           atorvastatin

In the first major trial of its kind, Cleveland Clinic researchers used a blinded rechallenge with atorvastatin or placebo to objectively confirm the presence of muscle-related symptoms in patients with a history of intolerance to multiple statins and found that evolocumab (a PCSK9 inhibitor) was a more effective option to lower cholesterol than ezetimibe in these patients.

The double-blinded, placebo-controlled clinical trial was designed with two stages:

• In Phase A, patients were assigned to two groups. Each group was treated for 10 weeks with atorvastatin or placebo in a blinded fashion, then crossed over to the alternate therapy for another 10 weeks. Patients were asked to report any muscle pain or weakness.
• Patients who reported intolerable muscle symptoms on atorvastatin, but not placebo, moved to Phase B. In this 24-week phase, patients with confirmed statin intolerance were administered two alternative non-statin therapies, ezetimibe vs. evolocumab.
• The research is being presented at the American College of Cardiology's 65th Annual Scientific Session and simultaneously published online in the Journal of the American Medical Association.
  "Statin intolerance has been a very challenging clinical problem," said Steven Nissen, M.D., chairman of Cardiovascular Medicine at Cleveland Clinic. "The study showed that PCSK9 inhibitors can significantly lower cholesterol in patients with documented statin intolerance, providing an effective treatment for these difficult to manage patients."
  The GAUSS-3 trial enrolled 511 patients with very high levels of LDL cholesterol - averaging more than 210 mg/dL ¬¬- and with a history of muscle-related statin intolerance. More than 80% of participants had previously reported intolerance to three or more statins. The study showed that 42.6 percent of these patients reported muscle pain or weakness on atorvastatin, but not placebo, and 26.5 percent on the placebo, but not atorvastatin.

Evolocumab could be more effective than ezetimibe in lowering cholesterol in statin-intolerant patients

Inhalable form of Ambrisentan drug could offer faster-acting treatment option for pulmonary edema

In a new study, researchers show an aerosolized, inhalable form of the drug Ambrisentan could offer a faster-acting treatment option for pulmonary edema, a life-threatening condition in which fluid accumulates in the lungs. Pulmonary edema is a significant risk for anyone spending time at high altitudes, and also affects people with chronic conditions including congestive heart failure and sickle cell anemia.

High altitude pulmonary edema, or HAPE, results when exposure to reduced oxygen levels causes the arteries in the lungs to constrict, which in turn causes blood pressure within the lungs to rise. Unchecked, this process leads to the rapid accumulation of fluid in the lungs, further reducing a person's ability to get oxygen and causing severe physical impairment.

Currently, Ambrisentan is available only in pill form and takes time to provide relief. The new study, conducted in rats, showed that delivering the drug via an inhaler achieved the same effect with just one-fifth of the typical oral dose.

"This mode of delivery gets the drug directly to the site of the problem—the lungs—providing relief much faster than the oral treatment," said Scott Ferguson, Ph.D. a postdoctoral researcher at the University of Colorado, Denver Anschutz Medical Center, who conducted the research. "Additionally, it requires a much lower dose, likely lowering the incidence of side effects and the cost of treatment."

Ferguson will present this research at the American Physiological Society Annual Meeting during Experimental Biology 2016.

Inhalable form of Ambrisentan drug could offer faster-acting treatment option for pulmonary edema

Adding liraglutide to diet and exercise plan may help people lose weight, reduce diabetes risk

In continuation of my update on liraglutide

For people with prediabetes who are overweight or obese, adding 3.0 mg of liraglutide for three years to a diet and exercise plan may lead to major health improvements, new industry-sponsored research suggests. The results will be presented Monday, April 4, at ENDO 2016, the annual meeting of the Endocrine Society, in Boston.

"Treatment with subcutaneous liraglutide 3.0 mg for three years, combined with a reduced-calorie diet and increased physical activity, can help people to not only lose weight, but also reduce the risk of Type 2 diabetes and improve cardiometabolic risk factors, which may ultimately reduce the risk of cardiovascular disease - the number one cause of death globally," said lead study author Ken Fujioka, MD, director of nutrition and metabolic research, and director for weight management at Scripps Research Institute in La Jolla, California.

"Type 2 diabetes is a major cause of death in the US. Both obesity, a chronic disease with serious health consequences, and prediabetes, typically defined as blood glucose concentrations that are higher than normal but lower than diabetes thresholds, increase the risk of developing Type 2 diabetes," Fujioka said. "For people with overweight or obesity and prediabetes, losing between 5 and 10 percent of their body weight can reduce their risk of Type 2 diabetes and other obesity-related health consequences."

Adding liraglutide to diet and exercise plan may help people lose weight, reduce diabetes risk

Researchers design more effective version of FDA-approved epilepsy drug with fewer side effects

Researchers at the University of Pittsburgh School of Medicine and Arts & Sciences have designed a more effective version of an FDA-approved epilepsy drug with the potential for fewer side effects, according to a study published on March 22 in Molecular Pharmacology. The experimental agent also could prove to be a treatment for tinnitus and other disorders caused by volatile neural signaling.

Epilepsy, in which erratic firing of nerve signals causes seizures, affects about 1 percent of people worldwide, said senior investigator Thanos Tzounopoulos, Ph.D., Endowed Chair in Auditory Physiology, associate professor of otolaryngology and member of the Auditory Research Group, University of Pittsburgh School of Medicine. Drugs to treat the disorder primarily work by influencing the transport of sodium, potassium and chloride ions across the nerve cell membrane to try to reduce the excitability of the brain cells.

"Unfortunately, these drugs don't work well in nearly a third of patients and there is a great need for better treatments," Dr. Tzounopoulos said. "We have been able to refine an existing medication so that it acts selectively on certain nerve cell membrane transport channels, which should make it more effective."

he available drug is called retigabine, and while it has improved symptoms for some patients, it can also lead to troublesome side effects, including retinal abnormalities, urinary retention and skin discoloration. Dr. Tzounopoulos was part of a study team that evaluated an earlier modification of retigabine, dubbed SF0034, which is being further developed by SciFluor Life Sciences LLC in Cambridge, Mass.

For the current project, Dr. Tzounopoulos and Peter Wipf, Ph.D., Distinguished University Professor of Chemistry at Pitt, rationally redesigned several structural components of retigabine to further increase its potency. Retigabine works by activating all five types of potassium transport channels in the KCNQ category, but only two of the potassium channels, KCNQ2/3, are important for stabilizing the cell membrane of brain cells involved in hyperexcitability-related disorders, such as epilepsy and tinnitus, Dr. Tzounopoulos explained. The new compound, known as RL648_81 ("RL-81"), targets just those channels.

When the researchers compared the three drugs head-to-head in lab tests, they found RL-81 was 15 times more potent than retigabine and three times more potent than SF0034. Because of its specificity, RL-81 also should have fewer side effects.

The experimental compound could also help people with tinnitus by preventing hyper-excitation of nerve cells in auditory pathways, Dr. Tzounopoulos noted.

       

Researchers design more effective version of FDA-approved epilepsy drug with fewer side effects

NTU researchers make breakthrough to tackle growing concern of antibiotic resistance

Scientists at Nanyang Technological University, Singapore (NTU Singapore) have discovered that antibiotics can continue to be effective if bacteria's cell-to-cell communication and ability to latch on to each other are disrupted.

This research breakthrough is a major step forward in tackling the growing concern of antibiotic resistance, opening up new treatment options for doctors to help patients fight against chronic and persistent bacterial infections.

The study, led by Assistant Professor Yang Liang from the Singapore Centre for Environmental Life Sciences (SCELSE) at NTU, found that a community of bacteria, known as biofilm, can put up a strong line of defence to resist antibiotics. The NTU team has successfully demonstrated how biofilms can be disrupted to let antibiotics continue their good work.

The research was published recently in Nature Communications, a prestigious academic journal by the Nature Publishing Group.

"Many types of bacteria that used to be easily killed by antibiotics have started to develop antibiotic resistance or tolerance, either through acquiring the antibiotic resistant genes or by forming biofilms," said Asst Prof Yang, who also teaches at NTU's School of Biological Sciences.

"The US Center for Disease Control estimates that over 60 per cent of all bacterial infections are related to biofilms. Our study has shown that by disrupting the cell-to-cell communication between bacteria and their ability to latch on to each other, we can compromise the biofilms, leaving the bacteria vulnerable and easily killed by antibiotics."

Bacterial resistance to antibiotics is rapidly growing world-wide and this puts at risk the ability to treat common infections in the community and hospitals.

The World Health Organisation states on its factsheet on Antimicrobial resistance that  "without urgent, coordinated action, the world is heading towards a post-antibiotic era, in which common infections and minor injuries, which have been treatable for decades, can once again kill".

Associate Professor Kevin Pethe, an expert in antibiotic development and infectious diseases from NTU's Lee Kong Chian School of Medicine, said that this discovery may yield new treatment options that doctors can employ against chronic and persistent bacterial infections.

"Being able to disable biofilms and its protective benefits for the bacteria is a big step towards tackling the growing concern of antibiotic resistance," said Assoc Prof Pethe.

"While the scientific community is developing new types of antibiotics and antimicrobial treatments, this discovery may help to buy time by improving the effectiveness of older drugs."

NTU researchers make breakthrough to tackle growing concern of antibiotic resistance

U of S-led researchers develop novel class of compounds for effective cancer treatment

A novel class of compounds developed by a University of Saskatchewan (U of S)-led research team could yield more effective and less toxic chemotherapy drugs to treat cancer.

Team leader Jonathan Dimmock, a medicinal chemistry researcher in the U of S College of Pharmacy and Nutrition, explained their compounds work by interacting with thiols, naturally occurring chemicals that perform several roles in cells.

The approach offers advantages over existing chemotherapy drugs which target nucleic acids found in DNA.

"Many of the compounds or drugs on the market are those that interfere with nucleic acids," Dimmock said. "These types of compounds can be very toxic and they can also cause problems of their own, like actually inducing cancer."

Thiols offer another approach. Among their many roles are defending cells against oxidization and modulating apoptosis—the process in which worn-out cells die. One of the hallmarks of cancer cells is they don't experience apoptosis and keep dividing out of control.

Umashankar Das, a research scientist in the Department of Chemical and Biological Engineering and long-time collaborator of Dimmock, explained that cancer cells produce an excess of thiols, such as one called glutathione. Knocking down levels of these thiols reduces cancer cells' ability to resist drugs.

"In cancer cells, glutathione expression is very high, which creates a defense mechanism," Das said. "Any anti-cancer compound that enters the cell cannot sustain its effect."

To address this, the team developed a two-stage attack, first knocking down thiol levels to make the cancer cells vulnerable, then hitting them again.

"Over the years, we've developed the theory of 'sequential cytotoxicity,' which simply means you give an initial attack on the cancer cell and then you give a second chemical attack," Dimmock said. "The cancer cells may be more vulnerable to the second attack than normal cells."

Designing molecules that selectively target thiols produced by cancer cells that cause drug resistance is the focus of many years' work by Dimmock, Das and their collaborators. In their latest study, they tested compounds against cells from nine different types of human cancer, including common types affecting blood, colon, breast, prostate, ovaries, kidneys, and lungs.

Das explained that since the compounds they've developed make cancer cells more sensitive to attack, they also remove resistance to standard chemotherapy drugs—a serious problem in current therapies.

U of S-led researchers develop novel class of compounds for effective cancer treatment

Plitidepsin in combination with dexamethasone shows top-line results in Phase III multiple myeloma trial

 

In continuation of my updates on  dexamethasone and Aplidin (plitidepsin) 

PharmaMar (MSE:PHM)  announced positive top-line results of its Phase III clinical trial -ADMYRE- with Aplidin (plitidepsin) in combination with dexamethasone versus dexamethasone alone in patients with relapsed/refractory multiple myeloma (MM). Aplidin® has shown a statistically significant 35% reduction in the risk of progression or death over the comparator (p=0.0054). The study has met its primary endpoint.

This pivotal, randomized, open-label, international, multicenter Phase III clinical trial, called ADMYRE, enrolled 255 patients in 83 medical centers across 19 countries (including the U.S, Europe and Asia-Pacific) with relapsed or relapsed and refractory multiple myeloma after at least three but no more than six prior therapeutic regimens.

The efficacy of plitidepsin in combination with dexamethasone versus dexamethasone alone has been evaluated by means of PFS calculated using the IMWG (International Myeloma Working Group) criteria and other secondary efficacy endpoints. A full description of the final ADMYRE data will be submitted for presentation at an upcoming medical meeting.

"Taking into account these positive results, we intend to submit a Marketing Authorization Application to the European Medicines Agency during the last quarter of this year", said Luis Mora, Managing Director of the Oncology Business Unit of PharmaMar, who added "I´d like to thank all the patients, physicians and the dedicated team at PharmaMar who helped participate in the success of this trial. Aplidin® may be our second drug of marine origin in the market".

As previously disclosed PharmaMar has entered into licensing agreements to market and distribute the drug candidate Aplidin with Specialised Therapeutics Asia, covering several Asian countries, Australia and New Zealand; with TTY Biopharm in Taiwan; and with a co-promotion agreement in 8 European countries with Chugai Pharma Europe.

Plitidepsin in combination with dexamethasone shows top-line results in Phase III multiple myeloma trial

Gleevec could be novel therapeutic agent for type 2 diabetes

The cancer treatment drug Imatinib, otherwise known as Gleevec is approved to treat various forms of cancer, mostly notably chronic myeloid leukemia (CML). However, researchers have stumbled onto another possible use for it, curing type 2 diabetes.

The team--made up of scientists from the Scripps Research Institute in United States, South Korea-based company Hyndai Pharm Co., Ltd., the Seoul National University, and Ulsan National Institute of Science and Technology (UNIST)--has identified for the first time that, through control of PPARγ, Gleevec lowers the level of insulin resistance, thereby reducing the risk of both hyperglycemia and obesity.

Acording to the team, led by Prof. Jang Hyun Choi (School of Life Sciences) of UNIST, "Although TZD-based medicines work effectively at improving glucose uptake by skeletal muscle and other peripheral tissues, due to increased risk of adverse effects they have been withdrawn from the market ." He continues, "In order to develop new type of medication that have fewer side effects, we have have discovered a new compound that can maintain stable blood sugar levels."

Among insulin-sensitizing drugs, TZDs are a therapeutic class that are selective agonists for PPARγ, which plays a central role in how the body metabolizes glucose, stores fat, and controls immune and inflammatory responses.

In the study, the team observed that the phosphorylation of PPARγ is closely related to developing diabetes. They also discovered that the removal of phosphoric acid from PPARγ shows anti-diabetic effects. To determine whether phosphoric acid is bound to PPARγ, the team developed a new chemical screening procedure. Using high throughput phosphorylation screening, the team discovered that Gleevec blocks CDK5-mediated PPARγ phosphorylation devoid of classical agonism as a PPARγ antagonist ligand.

Prof. Choi states, "Although studies have shown that Gleevec treatment may show improved insulin sensitivity and decrease blood glucose in patients with known diabetes, the exact cause hasn't been proven yet." He continues, "Through this research, we discovered Gleevec, which is used in leukemia medications, can inhibit the phosphorylation of PPARγ."

Gleevec could be novel therapeutic agent for type 2 diabetes

New drug regimens could significantly improve treatment for tuberculosis

Researchers from UCLA and Shanghai Jiao Tong University have made an important step toward a substantially faster and more effective treatment for tuberculosis, which infects some 10 million people and causes 1.5 million deaths each year.

Combination therapy, which utilizes a series of drugs, is a clinical standard for many major diseases. However, the number of potential combinations of different drugs and dose levels can be in the billions, making the prospect of choosing the best one seem daunting.

The research was published in the Proceedings of the National Academy of Sciences.

In the study, researchers used a technique called feedback system control, which was developed at UCLA, to study cells infected with the bacteria that cause tuberculosis. They quickly narrowed combinations of 14 different tuberculosis drugs with five different doses -- resulting in 6 billion possibilities -- into several promising combination treatments that kill the bacteria that cause tuberculosis much faster than the standard regimen used to treat tuberculosis.

"Designing a drug combination with optimized drug-dose ratios has, until now, been virtually impossible," said Chih-Ming Ho, the study's principal investigator and the Ben Rich-Lockheed Martin Chair Professor at UCLA's Henry Samueli School of Engineering and Applied Science. "Feedback system control technology demonstrated it can pinpoint these best possible ratios for a wide spectrum of diseases."

"If our findings are confirmed in human studies, the new drug regimens that we have identified should dramatically shorten the time needed to treat tuberculosis," said Dr. Marcus Horwitz, a senior author on the research and a distinguished professor of medicine and microbiology, immunology and molecular genetics at the UCLA David Geffen School of Medicine. "This will increase the likelihood of successful treatment and decrease the likelihood of patients developing drug-resistant tuberculosis. A highly successful and rapid treatment may hasten the eventual eradication of tuberculosis."

New drug regimens could significantly improve treatment for tuberculosis: Researchers from UCLA and Shanghai Jiao Tong University have made an important step toward a substantially faster and more effective treatment for tuberculosis, which infects some 10 million people and causes 1.5 million deaths each year.

Melatonin appears to suppress growth of breast cancer stem cells

In continuation of my update on Melatonin

Melatonin, a hormone produced in the human brain, appears to suppress the growth of breast cancer tumors.

Researchers at Michigan State University published this finding in the current issue ofGenes and Cancer. While treatments based on this key discovery are still years away, the results give scientists a key foundation on which to build future research.

"You can watch bears in the zoo, but you only understand bear behavior by seeing them in the wild," said David Arnosti, MSU biochemistry professor, director of MSU's Gene Expression in Development and Disease Initiative and co-author of the study. "Similarly, understanding the expression of genes in their natural environment reveals how they interact in disease settings. That's what is so special about this work."

The brain manufactures melatonin only at night to regulate sleep cycles. Epidemiologists and experimentalists have speculated that the lack of melatonin, due in part to our sleep-deprived modern society, put women at higher risk for breast cancer. The latest MSU study showed that melatonin suppresses the growth of breast cancer stem cells, providing scientific proof to support the growing body of anecdotal evidence on sleep deprivation.

The research team was led by Juliana Lopes, a visiting researcher from Sao Paolo, Brazil. Before the team could test its theory, the scientists had to grow tumors from stem cells, known as "mammospheres," a method perfected in the laboratory of James Trosko at MSU.

The growth of these mammospheres was enhanced with chemicals known to fuel tumor growth, namely, the natural hormone estrogen, and estrogen-like chemical Bisphenol A, or BPA, found in many types of plastic food packages.

Melatonin treatment significantly decreased the number and size of mammospheres when compared with the control group. Furthermore, when the cells were stimulated by estrogen or BPA and treated with melatonin at the same time, there was a greater reduction in the number and size of mammospheres.

"This work establishes the principal by which cancer stem cell growth may be regulated by natural hormones, and provides an important new technique to screen chemicals for cancer-promoting effects, as well as identify potential new drugs for use in the clinic," Trosko said.

Mycophenolate mofetil drug seems safe, effective in treating autoimmune hepatitis

New research indicates that mycophenolate mofetil, a drug that is usually used to prevent rejection after kidney, heart or liver transplant, seems safe and effective in treating autoimmune hepatitis (AIH), a serious chronic liver disease that mainly affects women. 

Treatment for AIH is usually based on steroids, which can have very serious side effects when taken long term either alone or in combination with the immunosuppressive drug azathioprine. In this latest real-world study, nearly 94% of patients had an initial complete response to mycophenolate mofetil mostly within 3 months of treatment. A total of 78 of 109 patients (72%) had a complete response on-treatment, and 61 of 78 (78%) maintained remission off steroids. Most importantly, mycophenolate mofetil as front-line treatment for AIH not only accomplished high rates of on-treatment response, but also showed the highest rates of maintenance of complete remission after complete drug withdrawal (75% of patients) ever published, for a median of 2 years.

"As relapse after drug withdrawal in AIH patients is almost universal with conventional therapy, mycophenolate mofetil seems a reasonable, safe, and important alternative first-line treatment of AIH that should seriously and urgently be considered in the future," said Dr. George Dalekos, senior author of the Alimentary Pharmacology & Therapeutics study.

Mycophenolate mofetil drug seems safe, effective in treating autoimmune hepatitis: New research indicates that mycophenolate mofetil, a drug that is usually used to prevent rejection after kidney, heart or liver transplant, seems safe and effective in treating autoimmune hepatitis (AIH), a serious chronic liver disease that mainly affects women.

Experimental drug may become key tool to target triple-negative breast cancer with immunotherapy

Previous studies at the University of Colorado Cancer Center show that the experimental drug AMPI-109 potently kills triple-negative breast cancer cells. But even the most compelling evidence of cell death in a dish isn't enough to push a drug into human clinical trials, even for triple-negative breast cancer, which has a high mortality rate and remains largely without targeted treatment options. Clinical trials are commonly guided by the knowledge of how a drug works - an understanding that can allow researchers to tweak a drug's effectiveness or explore rational combinations of multiple drugs to maximize antitumor responses. Now a study published in the journal Oncogenesis offers compelling evidence that AMPI-109 works by flipping the switch on an enzyme called PRL-3 that initially puts cancer cells to "sleep" or senescence, and shortly thereafter leads to their death, or apoptosis.

"For decades, we've known about a paradoxical signaling pathway called TNF-R1 whose activation can either help a cell survive or lead to cell death. However, the signals that lead to this pathway promoting survival or promoting death have been poorly understood, especially in the context of cancer cells. We have observed that one regulator of this process in triple-negative breast cancer cells may be the activity of PRL-3. With this gene active, cells survive. With PRL-3 inactivated, cells senesce and eventually die," says Hamid Gari, PhD, who studied the mechanism of PRL-3 while working as a doctoral candidate in the lab of CU Cancer Center investigator James R. Lambert, PhD. Gari is first author and Lambert is senior author of the current study which was performed in collaboration with Scott Lucia, MD in the department of Pathology.

Gari explains that PRL-3 sets in motion a set of genes that recruits elements of the immune system to boost cancer growth during good times and allows cancer cells to sleep through bad times, for example those caused by anti-cancer therapies.

"Hamid's studies knocked down the gene PRL-3 in triple-negative breast cancer cells using genetic techniques, but the drug does something analogous by blocking PRL-3 function. Our studies suggest AMPI-109 reprograms the cell to enter senescence but then they keep going past this state and into apoptosis," Lambert says.

The finding comes at a time when cancer immunotherapies are becoming first-line treatments for many forms of the disease. Basically, the strategy is to teach the immune system to recognize and attack tumor tissue. However, some cancers may be particularly good at "hiding" from the immune system, allowing them to subsist and thrive in challenging tumor tissue conditions. For this reason, many immunotherapies result in holding cancer at bay rather than wiping it out completely. In fact, some immunotherapies treat cancer as a chronic condition, with therapy continuing indefinitely with the goal of simply keeping cancer in check.

"Our studies propose that by inhibiting PRL-3 activity, such as with AMPI-109, it may serve as a 'flag' to signal the immune system where the tumor is, and in essence could sensitize tumors to immunotherapy. The result is a two-hit strategy to expose the tumor and then allow the immune system combat it," Gari says.

Ref : http://www.ncbi.nlm.nih.gov/pubmed/26909599?dopt=Abstract&holding=npg

Ref : http://www.nature.com/oncsis/journal/v5/n8/full/oncsis201650a.html#bib6

Experimental drug may become key tool to target triple-negative breast cancer with immunotherapy

Xalkori Approved For Rare Genetic Form of Lung Cancer

In continuation of my update on Xalkori (crizotinib)

Xalkori (crizotinib) has been approved by the U.S. Food and Drug Administration to treat advanced non-small cell lung cancer (NSCLC) with tumors that have a rare ROS-1 gene mutation.The drug was approved in 2011 to treat advanced NSCLC that was related to an abnormal ALK gene, the agency said Friday in a news release.

Lung cancer is the leading cause of cancer death in the United States. Last year, more than 221,000 cases were diagnosed and more than 158,000 people died from it, the FDA said.

Clinical studies of 50 people with ROS-1-positive NSCLC found that about two-thirds of participants treated with Xalkori had their tumors partially or completely shrink for an average of 18 months, the agency said.

The drug's most common side effects include nausea, diarrhea, vomiting, swelling, constipation, elevated liver enzymes, fatigue, loss of appetite and upper respiratory infection. More serious adverse reactions could include liver problems, lung inflammation, abnormal heartbeat and loss of vision.

Xalkori Approved For Rare Genetic Form of Lung Cancer