TAG: "Drugs"

Oxytocin shows promise for improving social skills in autistic mice

UCLA study could point way toward therapy for people with autism.

Daniel Geschwind, UCLA

By Mark Wheeler, UCLA

People with autism spectrum disorders have difficulty with social behavior and communication, which can make it challenging to form friendships, engage in routine conversations or pick up on the social cues that are second nature to most people. Similarly, mice with symptoms of autism show little interest in interacting or socializing with other mice.

A drug called risperidone has been shown to treat some symptoms of autism — including repetitive behaviors — in both humans and mice, but so far no medication has been found to help improve the ability to socialize.

In a study published online by the journal Science Translational Medicine, researchers at UCLA found that giving oxytocin to mice with autism-like symptoms restored their normal social behavior. Oxytocin is a neuropeptide, a type of molecule that helps neurons communicate with one another.

But perhaps the study’s biggest surprise was that early postnatal administration of the oxytocin led to longer-lasting positive effects, which continued into the animals’ adolescence and adulthood. “This suggests that there may be critical windows of time for treatment that are better than others,” said Daniel Geschwind, a UCLA professor of psychiatry, neurology and human genetics and senior author of the study.

In 2011, Geschwind and his colleagues developed a mouse model for autism spectrum disorders by knocking out a gene called contactin-associated protein-like 2, or CNTNAP2, which scientists believe plays an important role in the brain circuits responsible for language and speech. Previous research has linked common CNTNAP2 variants to a heightened risk for autism, while rare variants can lead to an inherited form of autism called cortical dysplasia-focal epilepsy syndrome.

“The oxytocin system is a key mediator of social behavior in mammals, including humans, for maternal behavior, mother–infant bonding, and social memory,” said Geschwind, who holds UCLA’s Gordon and Virginia MacDonald Distinguished Chair in Human Genetics and is the director of the Center for Autism Research and Treatment at the Semel Institute for Neuroscience and Human Behavior at UCLA. “So it seemed like a natural target for us to go after.”

The mice that were engineered for autism have fewer oxytocin neurons in the hypothalamus than other mice and lower-than-normal oxytocin levels throughout the brain. But after researchers treated them with oxytocin, the animals spent normal amounts of time interacting with other mice — the measure scientists used to gauge their sociability.

Separately, the researchers gave the mice melanocortin, an agonist that binds to specific receptors on a cell in order to activate it. They found that it caused a natural release of oxytocin from the mice’s brain cells, which also improved the mice’s sociability.

“The study shows that a primary deficit in oxytocin may cause the social problems in these mice, and that correcting this deficit can correct social behavior,” Geschwind said.

The next stage of the research, Geschwind said, will be to determine the lowest dosage of oxytocin that still proves effective. Because the mice in the study displayed symptoms similar to those of people on the autism spectrum, the researchers hope that this therapy may someday be applicable to humans.

The study was funded by the National Institute of Mental Health (R01 MH081754-02R, NIH/NS50220), the NIH Autism Centers of Excellence (HD055784-01 and 5R01-MH081754-04), the Simons Foundation Autism Research Initiative, Autism Speaks (7657), the NIH/National Institute of Neurological Disorders and Stroke (R01 NS049501 and R01 NS074312) and a McKnight Foundation Brain Disorders Award.

The study’s other authors were Olga Peñagarikano, María Lázaro, Xiao-Hong Lu, Hongmei Dong, Hoa Lam, Elior Peles, Nigel Maidment, Niall Murphy and X. William Yang, all of UCLA; Peyman Golshani of UCLA and the West Los Angeles V.A. Medical Center; and Aaron Gordon of Israel’s Weizmann Institute of Science.

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3-D enzyme model provides new tool for developing anti-inflammatory drugs

Models show how two PLA2 enzymes extract their substrates from cellular membranes.

By Heather Buschman, UC San Diego

Phospholipase A2 (PLA2) enzymes are known to play a role in many inflammatory diseases, including asthma, arthritis and atherosclerosis. It then stands to reason that PLA2 inhibitors could represent a new class of anti-inflammatory medication. To better understand PLA2 enzymes and help drive therapeutic drug development, researchers at the UC San Diego School of Medicine developed 3-D computer models that show exactly how two PLA2 enzymes extract their substrates from cellular membranes. The new tool is described in a paper published online the week of Jan. 26 by the Proceedings of the National Academy of Sciences.

“This is the first time experimental data and supercomputing technology have been used to visualize an enzyme interacting with a membrane,” said Edward A. Dennis, Ph.D., Distinguished Professor of Pharmacology, chemistry and biochemistry and senior author of the study. “In doing so, we discovered that binding the membrane triggers a conformational change in PLA2 enzymes and activates them. We also saw several important differences between the two PLA2 enzymes we studied — findings that could influence the design and development of specific PLA2 inhibitor drugs for each enzyme.”

The computer simulations of PLA2 enzymes developed by Dennis and his team, including first author Varnavas D. Mouchlis, PhD, show the specific molecular interactions between PLA2 enzymes and their substrate, arachidonic acid, as the enzymes suck it up from cellular membranes.

Make no mistake, though — the animations of PLA2 in action are not mere cartoons. They are sophisticated molecular dynamics simulations based upon previously published deuterium exchange mass spectrometry (DXMS) data on PLA2. DXMS is an experimental laboratory technique that provides molecular information about the interactions of these enzymes with membranes.

“The combination of rigorous experimental data and in silico [computer] models is a very powerful tool — the experimental data guided the development of accurate 3D models, demonstrating that these two scientific fields can inform one another,” Mouchlis said.

The liberation of arachidonic acid by PLA2 enzymes, as shown in these simulations, sets off a cascade of molecular events that result in inflammation. Aspirin and many other anti-inflammatory drugs work by inhibiting enzymes in this cascade that rely on PLA2 enzymes to provide them with arachidonic acid. That means PLA2 enzymes could potentially also be targeted to dampen inflammation at an earlier point in the process.

Co-authors include Denis Bucher, UC San Diego, and J. Andrew McCammon, UC San Diego and Howard Hughes Medical Institute.

This research was funded, in part, by the National Institute of General Medical Sciences at the National Institutes of Health (grants GM20501 and P41GM103712-S1), National Science Foundation (grant ACI-1053575) and Howard Hughes Medical Institute.

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How melanoma resists new drug combination therapy

UCLA discovery paves way for development of more effective patient-tailored therapies.

Roger Lo, UCLA

By Reggie Kumar, UCLA

Researchers at the UCLA Jonsson Comprehensive Cancer Center have uncovered how melanoma becomes resistant to a new drug combination therapy consisting of BRAF+MEK inhibitor — chemical compounds used to fight cancer.

During the two-year study led by Dr. Roger Lo, the research team took 43 tumor samples from 15 patients before they were prescribed the new BRAF+MEK inhibitors and then after the patients relapsed after the melanoma developed resistance to the drug therapy. The participants had all benefited from the combo therapy initially, but after a timeframe of a few months to more than a year, the tumors that had initially regressed, started to grow again.

After obtaining biopsies of the tumors, the researchers extracted and analyzed the genetic material. This analysis provided leads for the investigators to study how melanoma cells grown in Lo’s laboratory rewired their growth circuitry to get around the combo inhibitors.

Lo’s team found that the melanoma cells resist the combo therapy of BRAF+MEK inhibitors by developing highly unusual changes in certain key cancer genes. These signature changes or configurations not only mark the presence of drug resistance melanoma cells but also indicate to researchers potential new ways to shut them off.

“We need to find ways to go beyond the BRAF+MEK drug combination, by possibly finding a third drug, or alter how we prescribe the combo of drugs,” said Lo, UCLA assistant professor of dermatology. “The idea is to eventual suppress melanoma drug resistance even before it arises.”

“In most cases, melanoma eventually becomes resistant,” said Dr. Antoni Ribas, JCCC member and professor of hematology and oncology, and a co-author of the study. “We now understand the molecular basis of the resistance mechanisms, which leads to the planning of new treatment approaches to disable these mechanisms.”

An estimated 70,000 new cases of melanoma are diagnosed each year in the United States. Of those with advanced stage or metastatic melanoma, about 8,000 people will die of the disease each year. About 50 percent of people with metastatic melanoma, have tumors that harbor a mutated protein called a mutated BRAF protein. The presence of this mutated BRAF protein is what makes a patient with metastatic melanoma appropriate for the BRAF+MEK combo inhibitor therapy.

Lo and Ribas previously collaborated on several seminal drug resistance studies investigating how melanoma resisted the then-experimental drug PLX4032, which is now known as Zelboraf (vemurafenib) and was approved by the FDA in 2011.

These studies have provided critical insights that led to development of the current combo therapy for melanoma using BRAF+MEK inhibitors and additional on-going clinical trials. Lo hopes this new study will also lead to more effective therapies for patients.

“If we understand how a disease fights your therapy, then we can start to design more effective treatment strategies,” Lo said.

The study is published online today in the journal Cancer Cell.

The research was funded by the National Institutes of Health (NIH), the Melanoma Research Alliance, and Stand Up To Cancer.

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Century-old drug reverses autism-like symptoms

Suramin shows promise in fragile X mouse model.

By Scott LaFee, UC San Diego

Autism spectrum disorders (ASD) affect 1 to 2 percent of children in the United States. Hundreds of genetic and environmental factors have been shown to increase the risk of ASD. Researchers at UC San Diego School of Medicine previously reported that a drug used for almost a century to treat trypanosomiasis, or sleeping sickness, reversed environmental autism-like symptoms in mice.

Now, a new study published in this week’s online issue of Molecular Autism, suggests that a genetic form of autism-like symptoms in mice are also corrected with the drug, even when treatment was started in young adult mice.

The underlying mechanism, according to Robert K. Naviaux, M.D., Ph.D., the new study’s principal investigator and professor of medicine at UC San Diego, is a phenomenon he calls the cellular danger response (CDR). When cells are exposed to danger in the form of a virus, infection, toxin or even certain genetic mutations, they react defensively, shutting down ordinary activities and erecting barriers against the perceived threat. One consequence is that communication between cells is reduced, which the scientists say may interfere with brain development and function, leading to ASD.

Researchers treated a fragile X genetic mouse model, one of the most commonly studied mouse models of ASD, with suramin, a drug long used for sleeping sickness. The approach, called antipurinergic therapy or APT, blocked the CDR signal, allowing cells to restore normal communication and reversing ASD symptoms.

“Our data show that the efficacy of APT cuts across disease models in ASD. Both the environmental and genetic mouse models responded with a complete, or near complete, reversal of ASD symptoms,” Naviaux said. “APT seems to be a common denominator in improving social behavior and brain synaptic abnormalities in these ASD models.”

Weekly treatment with suramin in the fragile X genetic mouse model was started at 9 weeks of age, roughly equivalent to 18 years in humans. Metabolite analysis identified 20 biochemical pathways associated with symptom improvements, 17 of which have been reported in human ASD. The findings of the six-month study also support the hypothesis that disturbances in purinergic signaling – a regulator of cellular functions, and mitochondria (prime regulators of the CDR) – play a significant role in ASD.

Naviaux noted that suramin is not a drug that can be used for more than a few months without a risk of toxicity in humans. However, he said it is the first of its kind in a new class of drugs that may not need to be given chronically to produce beneficial effects. New antipurinergic medicines, he said, might be given once or intermittently to unblock metabolism, restore more normal neural network function, improve resilience and permit improved development in response to conventional, interdisciplinary therapies and natural play.

“Correcting abnormalities in a mouse is a long way from a cure in humans,” cautioned Naviaux, who is also co-director of the Mitochondrial and Metabolic Disease Center at UC San Diego, “but our study adds momentum to discoveries at the crossroads of genetics, metabolism, innate immunity, and the environment for several childhood chronic disorders. These crossroads represent new leads in our efforts to understand the origins of autism and to develop treatments for children and adults with ASD.”

Co-authors include Jane C. Naviaux, Lin Wang, Kefeng Li, A. Taylor Bright, William A. Alaynick, Kenneth R. Williams and Susan B. Powell, all at UC San Diego.

This study was supported, in part, by the Jane Botsford Johnson Foundation, the UC San Diego Christini Foundation, the UC San Diego Mitochondrial Research Fund, and the Wright Family Foundation.

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UCLA, Yale profs propose new regulations for off-label uses of drugs, devices

Health care providers have had to make their own decisions about using drugs off-label.

Ryan Abbott, UCLA

By Enrique Rivero, UCLA

Off-label use of drugs and medical devices — using approved remedies in unapproved ways — has long been a part of medicine. The practice provides public health benefits but also presents some risks.

For the most part, the U.S. Food and Drug Administration allows physicians to prescribe drugs and devices off-label in the same way they are prescribed for their approved uses. The FDA couldn’t require approval for each off-label use because the burden for approval would be so high that few off-label uses would be approved, which would deprive patients of effective treatments for which the drugs weren’t originally intended.

As a result, health care providers have had to make their own decisions about using drugs off-label, often in the face of uncertain evidence.

To address that issue, researchers from the David Geffen School of Medicine at UCLA have proposed a system combining reporting, testing and enforcement regulations, and allowing interim periods of off-label drug prescription. Their recommendations, published in the Duke Law Journal, would give patients more treatment options while providing regulators with evidence of the drugs’ safety and efficacy.

Much off-label prescribing of medications and medical devices is beneficial, but without rigorous study it is difficult to know what works and what doesn’t, said Dr. Ryan Abbott, visiting assistant professor of medicine in UCLA’s division of general internal medicine and health services research.

“Even though a drug or device has been approved for one indication, physicians can prescribe them for other uses as well — it’s been part of medical practice for a long time,” said Abbott, a physician and attorney who co-wrote the paper with Yale Law School’s Ian Ayres. “Our proposals are important because there is a tension between providing access to the drugs and devices that could benefit patients in untested ways and the need to prevent harmful uses.”

The authors’ proposal comprises three elements:

  • Improved reporting of off-label use through disclosure of diagnostic codes in reports to the FDA, in detailing data that pharmaceutical companies obtain on physicians’ prescribing habits, and in reports to the FDA and Medicare/Medicaid reimbursement requests. This information, which would omit details that could identify individual patients, could then be shared with academics and pharmaceutical companies for use in research.
  • Expansion of post-market testing requirements for off-label use of drugs and medical devices.
  • A tiered labeling system for drugs consisting of “red box” warnings that prohibit certain off-label uses; informed consent from patients receiving prescriptions for off-label use of some drugs that currently carry “black box” warnings, which identify drugs that pose a significant risk of serious or life-threatening adverse effects; and the creation of a new “grey box” warning that blocks Medicare Part D and Medicaid reimbursements by the Centers for Medicare and Medicaid Services.

“The improved reporting, testing and enforcement regulation would work together to produce a more layered range of regulatory responses,” the authors write. “The FDA, armed with better information about the extent of off-label use and adverse effects, would be in a better position to require post-market testing and to discourage off-label use with new types of warnings if manufacturers fail to provide sufficient, timely evidence of safety and efficacy in that particular extrapolation.”

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Drug reduces diabetes symptoms in mice

Research involves a potent enzyme inhibitor discovered at UC Davis.

Bruce Hammock, UC Davis

Can diabetes be prevented and even reversed?

Yes, it can — at least in genetically obese mice, according to a newly published study by led by researchers Bruce Hammock at the University of California, Davis, and Joan Clària at the University of Barcelona. The research involves a potent enzyme inhibitor discovered by Hammock’s laboratory that dramatically reduces inflammation, inflammatory pain and neuropathic pain.

In the study, published in the Proceedings of the National Academy of Sciences, an enzyme called soluble epoxide hydrolase, or sEH, inhibitor both prevented the onset of diabetes and reversed the effects of diabetes in obese mice.

“Our previous studies show the drug we are working on will reduce the symptoms of diabetes in mice by itself,” Hammock said, “but the excitement about Joan Clària’s work is that if the mice have a genetically increased level of omega-3 fatty acids — the drug offers prevention or cure in mice.”

The Centers for Disease Control and Prevention estimates that 29.1 million Americans, or 9.3 percent of the population, have diabetes, which is characterized by abnormal blood glucose levels. This includes 8.1 million undiagnosed cases.

The new drug apparently works by stabilizing metabolites of an omega-3 fatty acid called DHA. These metabolites are thought to contribute to the beneficial effects of a diet high in omega-3 fatty acids, Hammock said. Previous UC Davis research in the laboratories of Hammock, Nipavan Chiamvimonvat, Robert Weiss, Anne Knowlton and Fawaz Haj showed that the enzyme reduces or reverses such diabetes-linked medical issues as renal failure, hypertension, diabetic pain, hardening of the arteries and heart failure.

“This exciting research brings mechanistic detail to understanding how omega-3 fatty acids in the diet exert important health effects,” said J. Bruce German, director of the UC Davis Foods for Health Institute, Department of Food Science and Technology, who was not involved in the diabetes-based research.

Clària is an associate professor at the Barcelona University School of Medicine and a senior consultant at the Biochemistry and Molecular Genetics Service of the Hospital Clínic of Barcelona.

In the paper, titled “Inhibition of Soluble Epoxide Hydrolase Modulates Inflammation and Autophagy in Obese Adipose Tissue and Liver: Role for Omega-3 Epoxides,” Clària described the administration of the sEH inhibitor as “a promising strategy to prevent obesity-related co-morbidities.”

Clària said the study also sheds more light on the role of sEH and omega-3 epoxides in insulin-sensitive tissues, especially the liver.

In addition to Clària and Hammock, the publication was first-authored by Cristina López-Vicario and co-authored by José Alcaraz-Quiles, Verónica García-Alonso, Bibiana Rius, Aritz Lopategi, Ester Titos  and Vicente Arroyo,  all of the Clària lab or associates; and Sung Hee Hwang of the Hammock Lab, UC Davis Department of Entomology and Nematology, and the UC Davis  Comprehensive Cancer Center.

Hammock is the founder and CEO of a start-up company, EicOsis, which is putting the new compounds into clinical trials for companion animals and the Pre-Investigational New Drug Application, or Pre-IND, Consultation Program for neuropathic pain in human diabetics.

The study was funded by Clària’s Spanish-initiated grants and by Hammock’s Research Project Grant (R01) and Superfund grants from the National Institutes of Health.

More information about the Hammock lab and about the Clària lab.

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Study IDs patients at higher risk for overdose from prescription painkillers

Study is first to examine factors associated with opioid dose escalation in first year of use.

Stephen Henry, UC Davis

By Karen Finney, UC Davis

Patients started on prescription painkillers who have substance-use disorders or who frequently contact their doctors’ offices are at greater risk of having their medication doses increase early in therapy, also increasing their risk of opioid-related overdose or death, UC Davis Health System researchers have found.

Published online in the journal Pain Medicine, the study is the first to examine factors associated with opioid dose escalation during the first year of use and may help physicians identify patients who should not continue taking medications such as hydrocodone, codeine or oxycodone.

“Most physicians recognize that they need to carefully monitor patients who are prescribed high doses of opioid pain medication, but patients nearly always start these medications at lower doses and increase to more dangerous levels over time,” said Stephen Henry, assistant professor of general medicine and lead author of the study. “We wanted to develop a more complete picture of the patients who should raise red flags early in the course of pain therapy, before their dose levels put them at high risk of overdose or death.”

Henry and his colleagues evaluated the medical records of nearly 250 adult patients given opioid painkillers for musculoskeletal pain between July 2011 and June 2012, but not during the prior year. They then compared those whose doses escalated with those whose doses remained stable in terms of diagnoses, medications, number and type of health care encounters, and demographics such as age, race and gender.

Two significant differences emerged: Patients whose doses escalated were more likely to have been previously diagnosed with a substance-use disorder (17 percent versus 1 percent) or they had more frequent communication with their doctors’ offices (an average of 16 additional encounters). Many of those additional encounters were via telephone or email, rather than in person.

Henry hopes the study results can help primary care physicians, who write the vast majority of pain medicine prescriptions, identify patients whose opioid use needs to be re-evaluated and whose pain may be better treated with non-opioid medications.

“Conversations with patients about pain medicine can be uncomfortable, in part because physicians have a hard time predicting who is likely to be a problem user and who isn’t,” said Henry, whose research focuses on addressing pain in primary care settings. “We hope our study can help minimize the number of patients who progress to high medication doses and eventually help reduce the number of patients harmed by these medications.”

Henry’s co-authors on the study were Barth Wilsey, Joy Melnikow and Ana-Maria Iosif of UC Davis. Wilsey is also a physician with the VA Northern California Health Care System.

The study, “Dose Escalation During the First Year of Long-Term Opioid Therapy for Chronic Pain,” was funded by the UC Davis Center for Healthcare Policy and Research and National Center for Advancing Translational Sciences (grants UL1 TR000002 and KL2 TR000134). It is available online at http://onlinelibrary.wiley.com/doi/10.1111/pme.12634/pdf.

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‘Cellular backpacks’ can provide therapy and relief for a host of conditions

Targeted drug delivery could help lead to more effective doses.

By Sonia Fernandez, UC Santa Barbara

Inflammation is a normal and often beneficial response to injury or infection. The swelling, heat and even pain are the body’s attempts to protect its soft tissue, remove offending objects, substances or microbes and initiate healing. However, persistent inflammation is often indicative of more serious conditions and can lead to problems of its own, including impaired healing, loss of function or even tissue death.

“Many diseases result in inflammation,” said Samir Mitragotri, professor of chemical engineering at UC Santa Barbara and director of the campus’s Center for Bioengineering. Whether inflammation is a byproduct of the disease or the inflammation is the disease, it is a common indicator of a problem with the system. “If we could target the common denominator, whether the inflammation is coming from cancer or arthritis, we could deliver the drug there,” said Mitragotri, who specializes in targeted drug delivery.

By taking advantage of natural body processes, researchers at UC Santa Barbara and MIT have developed a method of targeting inflamed tissues, creating a way to treat both the inflammation and its underlying cause.

“It’s a cell-mediated approach to targeted drug delivery,” said UCSB grad student researcher Aaron Anselmo, lead author of a study in the current issue of the Journal of Controlled Release.

Key to this technology is the utilization of monocytes, the type of white blood cell known for its ability to penetrate into deep sections of tissue. Under normal circumstances, the job of these monocytes is to circulate in the blood and respond to biochemical signals that indicate inflammation — a sign of injury or infection. Once at the site, these monocytes transform into macrophages, cells that reside in the affected tissues to engulf and digest foreign material.

Working with the expertise of chemical engineering and materials science researchers at MIT, including graduate researcher Jonathan Gilbert and professors Robert Cohen and Michael Rubner, the UCSB researchers developed an approach based on “cellular backpacks” — flat, disc-shaped polymeric particles that could, in the near future, hold therapeutic agents that can be released at the site of the inflammation. These polymeric discs are coated on one side with a single layer of an antibody that can bind to receptors on the monocyte’s surface.

To prevent the cellular backpack from being engulfed and devoured by the very cell that is transporting it, the researchers chose a flexible particle that is nonspherical in shape, which, according to the study, has proved to be more durable and resistant to phagocytosis than a rigid spherical particle. The shape and flexibility gives the backpack the ability to bind strongly while resisting phagocytosis to hitchhike onto monocytes and reach the inflamed tissue.

In-vitro and in-vivo tests have proved that cellular backpacks are successful in attaching to and being transported by monocytes to target areas without impairing the monocytes’ natural functions, said Anselmo. Further studies will include research into how much drug can be loaded into the cellular backpacks. Ideally, Anselmo said, the cellular backpacks loaded with drugs would be injected into the bloodstream, whereupon they would attach to these traveling monocytes and hitchhike to the target region. At the inflamed site, the particles would simultaneously degrade and release their drugs.

The development of effective cellular backpacks has broad potential, say the researchers.

“Basically the main benefit is that you can deliver the drug in a more effective dose,” Mitragotri said. Take for example the case of chemotherapy, which often has a narrow therapeutic range: Too little and the treatment is not effective, too much and it can be lethal. Because chemo travels through the bloodstream and affects all the tissues it comes in contact with, dosages are restricted at least in part based on the deleterious effect it has on other, unafflicted organs and their functions. Not only can targeted therapy ensure other body systems remain unaffected, Mitragotri explained, but it could allow for higher doses of drug to the site, which could decrease treatment time.

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Grant will explore ways to speed Ebola drug production

UC Davis team will attempt to produce antibodies from plant cells grown in bioreactors.

Researchers at the University of California, Davis, will explore ways to speed production of the Ebola drug Zmapp with a $200,000 rapid-response grant from the National Science Foundation.

Developed by Mapp Biopharmaceutical Inc. of San Diego, in collaboration with the U.S. government and partners in Canada, Zmapp is a cocktail of antibodies produced in and extracted from whole tobacco plants. The UC Davis team, including plant scientists, molecular biologists and chemical engineers, will attempt to produce the antibodies from plant cells grown in bioreactors instead of in whole plants.

Extracting the drug from whole plants is a proven process but production capacity is limited at this time, said Karen McDonald, professor of chemical engineering and materials science.

“Whereas if we can produce it in a bioreactor, a lot of biotech companies and contract manufacturers can do that, and it would allow for much more rapid production,” McDonald said.

Mapp’s technology uses a type of bacteria to transiently transfer the monoclonal antibodies’ DNA into plants. The plants do not permanently carry the new DNA or pass it on to the next generation. A week or so after the transfer, the plants are ground up to extract the monoclonal antibodies.

The UC Davis team will use the same type of bacteria to infect plant cells, then attempt to grow them in the laboratory, starting with volumes of a few liters and scaling up to a 100-liter bioreactor. Biotech companies use similar methods to produce drugs and vaccines from cultures of animal cells, bacteria and yeast.

“This is about proof of concept,” said Somen Nandi, managing director of the Global HealthShare Initiative at UC Davis, which aims to speed development of low-cost health care solutions for developing countries, including a rabies vaccine grown in tobacco plants. If successful, the technique could potentially be applied to other antibodies used as drugs or vaccines.

Other team members are Ray Rodriguez, UC Davis professor of molecular cell biology and director of the Global HealthShare Initiative; Abhaya Dandekar, UC Davis professor of plant sciences; and professor Kazuhito Fujiyama, Osaka University, Japan.

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Combination drug therapy shows promise for women with advanced breast cancer

Study shows benefits of combining palbociclib, letrozole for treating advanced breast cancer.

Dennis Slamon (left) and Richard Finn, UCLA

By Reggie Kumar, UCLA

In a groundbreaking study that offers new hope for women with advanced breast cancer, researchers from UCLA’s Jonsson Comprehensive Cancer Center have published final clinical trial results that showed the amount of time women with advanced breast cancer were on treatment without their cancer worsening was effectively doubled when they took the experimental drug palbociclib.

An investigational drug discovered and being developed by Pfizer Inc., palbociclib targets a key family of proteins (CDK4/6) responsible for cell growth and prevents them from dividing. Results of the multiyear phase two study showed a significant increase in progression-free survival — the length of time a patient is on treatment without tumor growth — for women with advanced breast cancer that was estrogen receptor-positive, HER2-negative, who were given a combination of the standard anti-estrogen treatment, letrozole, and palbociclib compared to letrozole alone.

“We’re essentially putting the brakes on cell proliferation and causing these tumor cells to stop growing,” said Dr. Richard Finn, associate professor of medicine at UCLA and lead author of the study.

The study was published online Dec. 15 ahead of print in the journal The Lancet Oncology.

Unlocking the power of palbociclib

The origin of the research dates to 2007, when Finn and cancer pioneer Dr. Dennis Slamon, UCLA professor of medicine and director of the Revlon/UCLA Women’s Cancer Research Program, held a meeting with Pfizer to discuss palbociclib and other experimental drugs in the company’s pipeline.

Preclinical work testing the drug in a panel of human breast cancer cells growing in culture dishes showed very encouraging activity, specifically against estrogen receptor-positive cancer cells. This led to clinical study collaboration with Pfizer led by Finn and built on laboratory work directed by Slamon at the Translational Oncology Research Laboratory at UCLA.

“When we studied palbociclib, we found that signal inhibition [of CDK4/6] in breast cancer hadn’t been seen before, or had been looked at but missed,” Slamon said. “That’s what really got us on the track.”

Once the Phase 1 study was completed and showed that the drug was safe, the phase two study was performed in 165 post-menopausal women with breast cancer who had advanced estrogen receptor-positive, HER2-negative disease.

Phase two results showed progression-free survival was 20.2 months for patients who received palbociclib plus letrozole and 10.2 months for those who received letrozole only. The results indicated a 51 percent reduction in the risk of disease progression with the addition of palbociclib to letrozole.

“What is really remarkable is that we doubled the median progression-free survival,” Finn said. “With the addition of palbociclib, PFS effectively doubled. That type of result is not often seen in cancer medicine.”

Results found that more than 80 percent of the women with metastatic estrogen receptor-positive breast cancer in the study received some benefit from this treatment, Finn and Slamon said. The drug doesn’t have the side effects, such as infections, of traditional chemotherapy, but does result in a lowered white blood cell count, which was very manageable.

A phase three international clinical trial of the drug conducted by Finn and Slamon with Pfizer in 660 women with estrogen receptor-positive, HER2-negative advanced breast cancer is ongoing.

Because so many of the women in the early testing showed significant long-lasting responses, the FDA granted palbociclib  “breakthrough therapy” status in late 2013.

Patient given second chance at life

Gloria Zollar, 78, mother of five, joined the phase two clinical trial in August 2010, after her UCLA oncologist discovered that her advanced breast cancer had spread to her bones.

Only one year later, doctors noticed that her tumors had stopped progressing, which allowed Zollar to remain active and continue playing golf.

“I am now in remission, and everyday I’m thankful to God that I’m alive and able to see my great-grandchildren and spend time with them,” said Zollar, who remains on the treatment.

With FDA having granted palbociclib “breakthrough therapy” status in late 2013, Zollar hopes the drug is made available to other patients battling this deadly disease.

“I am very pleased that other women could have a second chance at life like many of us who participated in the trial.”

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FDA approves drug that extends survival in most common type of lung cancer

Drug offers new hope for people with lung cancer who often have few treatment options.

Edward Garon, UCLA

By Peter Bracke, UCLA

The Food and Drug Administration today (Dec. 12) approved a new drug to treat non-small-cell lung cancer (NSCLC), offering people new hope in fighting the disease. Lung cancer is expected to lead to more than 150,000 deaths in the United States this year alone, and NSCLC accounts for about 85 percent of all lung cancers. The drug, Cyramza (ramucirumab), was tested on more than 1,200 people with NSCLC whose cancer worsened during or after first-line chemotherapy. The research was conducted as part of a multiyear, phase three clinical trial at UCLA and other centers in 26 countries on six continents. This is the first study in a decade to demonstrate a survival benefit in people with that type of lung cancer who had already received treatments.

Cyramza is an antibody that targets the extracellular domain of VEGFR-2, an important protein in the formation of vessels that supply blood to cancer cells. Patients were given the experimental drug in combination with docetaxel, a clinically approved therapy that is considered the cornerstone of second-line treatment in advanced NSCLC, said Dr. Edward Garon, the study’s principal investigator and a researcher at the UCLA Jonsson Comprehensive Cancer Center. Results of the study were recently published by Garon and colleagues in The Lancet.

The standard treatment regimen for people whose cancer worsens during or after initial therapy is chemotherapy with a single drug. This is a patient population for whom survival is typically several months, with approximately only 10 percent of patients responding to therapy.

The percentage of people who responded to treatment and the period of time before the disease worsened were both greater when Cyramza was added to docetaxel compared to what was seen with docetaxel alone, Garon said. In the study, 23 percent of patients responded to the combination of Cyramza and docetaxel, meaning that their tumors shrank more than a specific threshold used in clinical trials. Overall, the median survival was more than 10 months.

”It is exciting to see that by adding ramucirumab (Cyramza) to docetaxel, patients were able to live longer than those who were treated with the standard approach,” Garon said. “We are pleased to have access to a drug that lengthens survival time in a population of lung cancer patients who often have few treatment options.”

Although adverse effects were experienced by patients, most commonly neutropenia (low levels of white blood cell that fight infection), fatigue and high blood pressure, these were largely manageable with appropriate dose reductions and supportive care, and without substantial reduction in planned dose intensity.

Garon said that in the future Cyramza will be evaluated in combination with other drugs to treat lung cancer. In addition, he noted that efforts are underway to understand which patients are most likely to benefit when Cyramza is added to docetaxel.

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To stop spread of HIV, African governments should target hot zones

UCLA develops strategy using a complex mathematical model.

By Mark Wheeler, UCLA

While Ebola has attracted much of the world’s attention recently, a severe HIV epidemic rages on around the world and in sub-Saharan Africa in particular. Globally, more than 34 million people are infected with HIV; in sub-Saharan Africa alone, 3 million new infections occur annually.

In an attempt to stop the spread of HIV, governments in the region are considering providing antiretroviral drugs to people who do not have the virus but are at risk for becoming infected. Such drugs are known as pre-exposure prophylaxis, or PrEP.

Although the conventional strategy — attempting to attempt to distribute the drugs to people in every city and village — might seem logical and equitable, researchers at UCLA have devised a plan they say would be much more effective in reducing HIV transmission.

The strategy, developed using a complex mathematical model, focuses on targeting “hot zones,” areas where the risk of HIV infection is much higher than the national average. In South Africa, where 17 percent of the population is infected with HIV, the model predicted that targeting hot zones would prevent 40 percent more HIV infections than using the conventional strategy — and would therefore be 40 percent more cost-effective.

“Stopping the HIV pandemic is one of the greatest challenges facing the global community,” said Sally Blower, the paper’s senior author and the director of the Center for Biomedical Modeling at the UCLA Semel Institute for Neuroscience and Human Behavior.

The report appears in the current online edition of Nature Communications.

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