TAG: "Drugs"

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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Researchers ID chemical compound that decreases effects of MS


UC Riverside-led study shows the ligand indazole choloride improves motor function.

Seema Tiwari-Woodruff, UC Riverside (Photo by Iqbal Pittalwala, UC Riverside)

By Iqbal Pittalwala, UC Riverside

Multiple sclerosis (MS), an autoimmune disease of the brain and spinal cord, affects about 2.3 million people worldwide (400,000 in the United States). Affecting more women than men, it can be seen at any age, although it is most commonly diagnosed between the ages of 20 and 40.

An unpredictable disease that disrupts the flow of information within the brain and between the brain and the body, MS is triggered when the immune system attacks the myelin sheath, the protective covering around the axons of nerve fibers. The “demyelination” that follows causes a disruption of nerve impulses. As the protective sheath – best imagined as the insulating material around an electrical wire – wears off, the nerve signals slow down or stop, and the patient’s vision, sensation and use of limbs get impaired. Permanent paralysis can result when the nerve fibers are completely damaged by the disease.

Given such debilitating effects, an aggressive search is on among scientists to find a cure for MS. Currently available therapies are only partially effective, however, in preventing the onset of permanent disability in MS patients. What would be immensely helpful is a drug that could minimize the degeneration of axons, thus reducing the rate and degree of MS progression. Better still would be if this drug could stimulate “remyelination,” the re-sheathing of the axons, restoring fast and uninterrupted flow of nerve impulses.

Now a team of researchers, led by a biomedical scientist at the University of California, Riverside, reports in this week’s issue of the Proceedings of the National Academy of Sciences that it has identified just such a drug in the lab: indazole chloride (Ind-Cl).

“This drug, which we administered on transgenic mice, can potentially halt the symptoms and reverse ongoing motor deficit due to MS,” said Seema K. Tiwari-Woodruff, an associate professor in the UC Riverside School of Medicine whose lab led the study.  “Our study shows that Ind-Cl can remyelinate axons which have gotten injured not just in MS but also traumatic brain injury and spinal cord injury.”

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Scientists discover why some patients respond to a life-saving melanoma drug


UCLA findings will help physicians determine the best treatment for patients.

UCLA Jonsson Comprehensive Cancer Center members Dr. Paul Tumeh and Dr. Antoni Ribas

By Reggie Kumar, UCLA

UCLA researchers have pioneered a new methodology to predict why some patients battling advanced melanoma respond well and others do not to the new breakthrough drug pembrolizumab.

The study, led by UCLA Jonsson Comprehensive Cancer Center members Dr. Paul Tumeh and Dr. Antoni Ribas, primary investigator of pembrolizumab, is the first of its kind since the U.S.Food and Drug Administration approved its use under the name Keytruda in September, and it could lead the way for more effective use of the drug in patients with melanoma and other cancers.

A protein known as PD-1 puts the immune system’s brakes on, preventing T cells from attacking cancer cells. Pembrolizumab removes the brake lines, freeing up the immune system to kill cancer cells.

“We’ve had amazing clinical success treating patients battling advanced melanoma with pembrolizumab. The challenge is that it only works in approximately 30 percent of patients with melanoma,” said Tumeh, lead author of the study and UCLA assistant professor of dermatology. “To address this challenge, we developed an approach that can select for patients who are likely to respond to this therapeutic class.”

During the two-year study, Tumeh and Ribas analyzed 46 patients with advanced melanoma who were treated with pembrolizumab and who underwent tumor biopsies before and during treatment. They analyzed the biopsies and classified them according to whether the patient responded or not to pembrolizumab. In collaboration with Dr. David Elashoff, UCLA Jonsson Comprehensive Cancer Center member and adjunct professor of medicine, the information allowed them to develop an algorithm that could predict the likelihood of treatment success or failure.

“Our job was to figure out why some patients are predisposed to respond and others are not,” said Ribas, professor of hematology and oncology in the department of medicine. “Now with these results researchers can develop better drug combinations that are more effective, less costly and with fewer side effects.”

Fifteen additional tumor samples were obtained from patients given pembrolizumab in Paris, without Ribas’ team knowing what the clinical outcomes were. After applying their predictive algorithm Tumeh correctly predicted what would happen in 13 out of the 15 patient cases.

Keytruda was the first PD-1 immunotherapy drug approved by the FDA and there are eight others currently in clinical development. Ribas and Tumeh’s findings will help scientists and clinicians develop and correctly prescribe the best treatment for patients with melanoma and other cancers.

“The next big step is to classify the different types of patients who do not respond to pembrolizumab so we can develop drugs that can modulate the tumors in a way that makes them responsive to pembrolizumab,” said Tumeh.

The findings are reported online today (Nov. 26) ahead of print in the journal Nature.

This research was supported by Stand Up to Cancer and the National Institute of Health. Additional funding was provided by the UCLA Jonsson Comprehensive Cancer Center through philanthropy and other sources.

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New drugs from fish oil could air artery repair


Interdisciplinary collaboration key to translating academic research into tangible innovations.

Kevin Lance, a graduate student in Tejal Desai's lab, holds up a tiny "wrap" that could be placed around an artery or vein and slowly release a fish oil-derived drug to prevent vascular scarring. (Photo by Kathleen Masterson, UC San Francisco)

By Kathleen Masterson, UC San Francisco

Every year, more than a half-million Americans undergo procedures to have a narrowed coronary artery propped open with a small metal mesh tube, or stent. The procedure is common for certain patients who’ve experienced a heart attack or other arterial blockages, and it helps to restore blood flow.

But in about 1 in 4 cases (1 in 3 if it’s your leg artery), the vasculature tissue starts renarrowing again after the procedure, effectively regrowing the blockage. The problem of excessive vascular scarring isn’t limited to stents, but also affects many other common procedures such as angioplasty, bypass surgery, and placement of fistulas or grafts for patients on dialysis.

“When we operate on an artery it always causes an inflammatory reaction and a subsequent scarring response just like anywhere else on your body, even the skin,” said Michael S. Conte, M.D., chief of vascular & endovascular surgery at UCSF.

If this inflammation continues, the cells surrounding the tiny metal cage still treat the area as injured, and ultimately grow back in.

But a common class of naturally occurring molecules from fish oil could change all that.

It turns out that when the body heals naturally it’s a two-step process: first it generates compounds to promote inflammation, and when those wane, the body sends in a second set of compounds that actively stops inflammation.

These anti-inflammation signaling compounds are derived in the body from dietary fish oil, and Conte and collaborators Charles Serhan of Harvard University and Tejal Desai, Ph.D., chair of the UCSF Department of Bioengineering and Therapeutic Sciences, are using them to develop treatments to prevent ongoing inflammation in blood vessels.

Desai has been working on stents from a different angle; her lab at the School of Pharmacy focuses on therapeutic microtechnology and nanotechnology. If successful, their collaboration could help prevent arteries and veins from closing up again after surgeries, such as a stent implant or an angioplasty, a procedure where a balloon is temporarily inserted into the artery or vein to open it up.

“What we’re trying to do is turn an angioplasty into a mosquito bite: we want it to get injured and resolve, not get injured and scar,” said Conte.

Interdisciplinary collaboration like that of Desai and Conte is key to translating academic research into tangible innovations. Partnering with industry is also vital in getting technologies to patients: UCSF’s Innovation, Technology and Alliances supports hundreds of researchers to make science come alive by procuring licenses, partnering with industry sponsors and filing patents.

ITA helped Conte and Desai file a patent for their combination drug-device approach. Theirs is one of 48 patent filings this fiscal year, while overall UCSF holds a total of 631 active patents. Additionally, ITA negotiated nearly 400 industry-sponsored research deals and new clinical trial agreements.

Conte and Desai also won an NIH grant that specifically funds promising vascular research that could be translated into a medicinal use. The grant keeps them on a tight timeline to get their product up to speed for testing in humans.

To date, Conte has shown the drug reduces vascular scarring in mice and rabbits after they undergo an angioplasty. Not only did the drug lead to less scar tissue build-up, but they found a reduction in the presence of white cells weeks later, suggesting healing was accelerated.

With the help of UCSF’s Innovation, Technology & Alliances team, the researchers have filed a patent for their combination drug-device approach.

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Anti-leukemia drug also may work against ovarian cancer


Findings extend anti-cancer potential of monoclonal antibody developed at UC San Diego.

An antibody therapy already in clinical trials to treat chronic lymphocytic leukemia (CLL) also may prove effective against ovarian cancer – and likely other cancers as well, report researchers at the UC San Diego School of Medicine in a study published in today’s (Nov. 17) online early edition of the Proceedings of the National Academy of Sciences (PNAS).

The findings extend the anti-cancer potential of an experimental monoclonal antibody called cirmtuzumab, developed at UC San Diego Moores Cancer Center by Thomas Kipps, M.D., Ph.D., and colleagues. Cirmtuzumab is currently in a first-in-human phase one clinical trial to assess its safety and efficacy in treating CLL.

Cirmtuzumab targets ROR1, a protein used by embryonic cells during early development and exploited by cancer cells to promote tumor growth and metastasis, the latter being responsible for 90 percent of all cancer-related deaths.

Because normal adult cells do not express ROR1, scientists suspect ROR1 is a specific biomarker of cancer cells in general and cancer stem cells in particular. Because it appears to drive tumor growth and disease spread, they believe it also presents an excellent target for anti-cancer therapies. Earlier research by Kipps and colleagues has shown a link between ROR1 and both breast cancer and CLL.

In their latest PNAS paper, Kipps and colleagues investigated whether cirmtuzumab also might be effective against ovarian cancer, which has rebuffed efforts to find a cure or long-term remedy. Most ovarian cancer patients initially respond well to standard chemotherapy, sometimes appearing to become disease-free, but 85 percent relapse within two years after systemic treatment, often with a more aggressive and disseminated form of the disease.

More than 21,000 women are diagnosed with ovarian cancer annually; more than 14,000 die from the disease each year. The 5-year survival rate after diagnosis is 44.6 percent.

The Moores Cancer Center team found that ovarian cancer stem cells, which are thought to be responsible for cancer recurrence and metastasis and are largely resistant to standard chemotherapies, singularly express ROR1. Patients whose tumors had high levels of ROR1 experienced more aggressive forms of ovarian cancer. They had higher rates of relapse and shorter median survival times than patients with lower levels of ROR1.

“ROR1 is used by embryo cells to migrate and to develop new organs,” said Kipps. “Cancer stem cells subsequently use ROR1 for their own growth and dissemination throughout the body. They are essentially the seeds of the cancer. The more seeds a tumor has, the greater its ability to recur after therapy or metastasize.”

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Statins reverse learning disabilities caused by Noonan syndrome


UCLA mouse study shows drugs overcome mutation, even in adult brain.

Alcino Silva, UCLA

UCLA scientists have discovered that statins, a popular class of cholesterol drugs, reverse the learning disabilities caused by a genetic disorder called Noonan syndrome.

Their findings were published online Nov. 10 by the journal Nature Neuroscience.

The disorder, which is caused by a genetic mutation, can disrupt a child’s development in many ways. It often causes unusual facial features, short stature, heart defects and developmental delays, including learning disabilities. No treatment is currently available.

“Noonan syndrome affects 1 in 2,000 people, and up to half of these patients struggle with learning disabilities,” said Alcino Silva, the study’s principal investigator and a professor of neurobiology, psychiatry and psychology at the David Geffen School of Medicine at UCLA. “Our approach identified the mechanism causing the disease, as well as a treatment that reversed its effects in adult mice. We are excited about these findings because they suggest that the treatment we developed may help the millions of Noonan patients with intellectual disabilities.”

While many genes contribute to Noonan syndrome, there is one gene that causes about half of all cases. This gene encodes for a protein that regulates another protein called Ras, which controls how brain cells talk to each other, enabling learning to take place.

Working with first author Young-Seok Lee, Silva studied mice that were genetically engineered to develop Noonan syndrome. They discovered that the predominant mutation that leads to Noonan creates hyperactive Ras, which disrupts cellular conversations and undermines the learning process.

“The act of learning creates physical changes in the brain, much like grooves on a record,” said Silva, who also is a member of the UCLA Brain Research Institute and UCLA Integrative Center for Learning and Memory. “Surplus Ras tips the balance between switching signals on and off in the brain. This interrupts the delicate cell communication needed by the brain to record learned information.”

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Immunotherapy for cancer can be toxic with obesity


UC Davis researchers link increased body fat and lethal drug reactions in mice.

Annie Mirsoian, UC Davis

Immunotherapy that can be effective against tumors in young, thin mice can be lethal to obese ones, a new study by UC Davis researchers has found. The findings, published online today (Nov. 3) in The Journal of Experimental Medicine, suggest a possible link between body fat and the risk of toxicity from some types of immunotherapy.

The study comes at a time of great excitement about immunotherapy drugs, which are being developed and used increasingly against cancer, particularly in melanoma and kidney and prostate cancers. Immunotherapies use immune components, such as antibodies or cytokines, to stimulate or suppress the immune system to help the body recognize, fight and kill tumors.

Immunotherapies fall into many classes, including systemic stimulatory regimens, inhibitors of checkpoint blockade and cell-mediated vaccines. Despite the progress made in their development in the last decade, many of these agents induce severe, often limiting toxicities in patients, hindering their use. UC Davis researchers have been working with mouse models to determine if there is a subset of patients for whom certain types of immunotherapies are especially toxic.

“Cancer is primarily considered a disease of the aged, and yet preclinical studies generally use young, lean animal models that may not be reflective of the ‘typical’ cancer patient,” said study lead author Annie Mirsoian. “Aging is a dynamic process that is characterized by increases in inflammatory factors, as well as a shift in body composition, where there is a gradual loss of lean muscle mass and an increase in fat accumulation, which effect how the immune system functions.”

Mirsoian, part of the immunology graduate group in the UC Davis Department of Dermatology, said the study sought to determine if by adjusting the mouse model to more closely reflect the cancer patient phenotype (advanced age and  overweight), researchers could better understand the discrepancies between animal study outcomes and those in patients in the clinic. Their studies examined aged mice on standard diets and compared those to aged mice that were calorie-restricted throughout life.

The researchers found that calorie restriction plays a protective role against toxicity. When laboratory aged mice ate their standard diet freely throughout life, they became obese and ultimately experienced lethal adverse reactions after receiving a systemic immunotherapy regimen.

“We know that people who are obese in general are at higher risk for complications from surgery, radiation and chemotherapy,” said study co-author Arta Monjazeb, assistant professor in the UC Davis Department of Radiation Oncology. “We know that obese people have higher levels of inflammatory markers in their blood, but there is a lack of data examining the effects of obesity on cancer treatment outcomes.”

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Sleep researcher awarded federal grants totaling $2.7M


Research has implications for improving sleep and memory for aging adults, college students.

Sara Mednick, UC Riverside

UC Riverside psychologist Sara C. Mednick has been awarded nearly $2.7 million in federal grants to continue researching the neural mechanisms of learning and memory, which has implications for improving sleep and memory for aging adults and the health of college students who pop so-called “smart drugs.”

Mednick previously led a team whose groundbreaking research confirmed the mechanism that enables the brain to consolidate memory and found that Ambien, a commonly prescribed sleep aid, enhances the process.

The National Institute on Aging, the National Science Foundation and the Department of Defense-Office of Naval Research have awarded Mednick grants to support research into sleep processes that are important for learning and memory, and how those processes might be manipulated to improve both.

Supported by a five-year, $1.25 million grant from the National Institutes of Health-National Institute on Aging, Mednick is expanding on research published last year which demonstrated for the first time the critical role that sleep spindles play in consolidating memory in the hippocampus region of the brain. Her team also showed that pharmaceuticals could significantly improve that process, far more than sleep alone.

Sleep spindles are bursts of brain activity that last for a second or less during a specific stage of sleep. The hippocampus, part of the cerebral cortex, is important in the consolidation of information from short-term to long-term memory, and spatial navigation. The hippocampus is one of the first regions of the brain damaged by Alzheimer’s disease.

The new study, which began in fall 2013, will investigate doses of Ambien needed to boost sleep spindles and whether declarative memory – the ability to recall facts and knowledge – improves as well. The next study will test the same question in older adults.

“Older adults have poorer sleep and less sleep spindles. They also experience decreases in verbal memory,” Mednick explained. “Maybe these decreases in cognition are related to less sleep. A question we hope to answer is, can we slow the cognitive aging process?”

In another project, Mednick and UC Berkeley neuroscientist Michael Silver will share a $450,000, three-year grant from the National Science Foundation to study the role of neural transmitters that are known to be important for brain plasticity and memory consolidation.

The researchers will study whether a prescription drug used to treat dementia associated with Alzheimer’s disease and Parkinson’s disease – Rivastigmine – can improve declarative memory. Rivastigmine is known to activate acetylcholine, a neuromodulator known as the “memory molecule.” Acetylcholine plays a role in attention and arousal and works to activate muscles.

A $995,381 grant from the Office of Naval Research will support a study of the effects of psychostimulants such as Adderall and Ritalin – used to treat attention deficit hyperactivity disorder (ADHD) – on cognition and sleep.

“Off-label use of these drugs has been increasing dramatically in the college population, and there has been very little research on their impacts on healthy populations and on sleep,” Mednick said. “I am interested in how these drugs may be influencing sleep-dependent memory consolidation.”

The military is interested out of concern that the practice of giving so-called “go” and “no-go” pills to keep servicemen and women alert for long periods of time may affect cognition.

About one-third of college students – approximately 11 million young adults – take the ADHD medications without prescriptions, assuming that these so-called “smart drugs” will make them smarter and take the place of sleep, Mednick explained.

“Research shows they aren’t getting better grades, but they believe they will,” she said. This study will help determine if these drugs can replace sleep, “or if there is something so important about sleep that no pharmacological intervention can replace. What are the links between sleep disruption and cognitive decline?”

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Anti-cancer drug found effective vs. common stem cell transplant complication


Trial shows that bortezomib provides better outcomes than existing treatments.

Researchers at UC Davis have found that the drug bortezomib effectively treats chronic graft-versus-host disease (GVHD), a common and debilitating side effect from allogeneic hematopoietic stem cell transplants. The trial showed that bortezomib provides better outcomes than existing treatments and does not impair the immune response against residual cancer cells, or the graft-versus-tumor effect (GVT).

“Bortezomib helped a group of patients who desperately needed a treatment, having failed multiple different therapies,” said UC Davis hematologist and associate professor Mehrdad Abedi, lead author on the paper. “The drug fights chronic graft-versus host disease, and unlike other GVHD therapies such as steroid, cyclosporine or mycophenolate, it treats chronic GVHD without dampening the graft-versus-tumor effect, which can be critically important to help patients avoid relapse. In fact, because bortezomib is an anti-cancer drug, it potentially attacks cancer cells in its own right.”

The trial results were published in October in the journal Blood.

Chronic GVHD strikes patients who have received stem cell transplants from donors, commonly called allogeneic transplants. Although the transplants are close matches, they are not identical, and donor cells can attack the recipient, damaging skin, lungs, kidneys and other organs, which can be life threatening.

Developed by Millennium Pharmaceuticals, bortezomib has been used to treat multiple myeloma, leukemia and lymphoma. The drug also has been studied against acute GVHD, making it a promising option against the chronic version of the disease.

The researchers first studied bortezomib in mice, in which the drug delivered excellent results.

The investigation, in collaboration with William Murphy, professor and acting chair of the Department of Dermatology and a co-senior author, found that bortezomib suppresses the donor immune cells that cause GVHD.

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Scientists trying old weapon against deadly new target


Developed at UC San Diego more than a decade ago, brincidofovir takes on Ebola.

(From left) James Beadle and Karl Hostetler, UC San Diego (Photo by Ryan Parks, UC San Diego)

With the Ebola crisis ongoing, much attention is focused upon finding a drug capable of slowing – if not stopping – the infectious, deadly and terrifying virus.

There is Zmapp, of course, the experimental biopharmaceutical produced by a San Diego-based biotech firm that was used briefly before supplies ran out. There are other anti-Ebola drugs reportedly under development in Oregon, Canada and China.

And there is brincidofovir, a compound with a decidedly unwieldy name that was discovered more than a decade ago by researchers at UC San Diego. Brincidofovir (pronounced brin-SIGH-doh-fo-veer) wasn’t invented to fight Ebola – the scientists were actually looking for a new way to fend off the menace of bioterrorism – but it may represent one of the best chances yet to conquer a virus that has killed more than 4,500 people, almost all in stricken West Africa.

In 1999, Dr. Karl Hostetler, then a professor of medicine in UC San Diego School of Medicine, got a call from officials at the National Institute of Allergy and Infectious Diseases. They posed a question: Could he help create a new drug to protect Americans if bioterrorists unleashed smallpox – the one-time global scourge now restricted to a few high-security labs?

There was already a drug called cidofovir that might serve, but it required an injection. NIAID officials wanted a pill, something safe, stable and broadly effective against not just smallpox, but other highly infectious, deadly viruses that might be deployed as bioweapons.

“There was a lot of talk and fear about such attacks at the time,” recalled Hostetler, now professor emeritus. “It’s still a legitimate concern.”

Hostetler, who studied the lipid molecules necessary to build cell membranes and was working on improved ways to deliver therapeutic drugs inside cells, agreed to help. Funding from NIAID arrived within days.

Over the next few years, he and colleagues created multiple analogs or variations of cidofovir. The first was brincidofovir. In cultured cell tests, the compound proved active against an array of viruses, blocking their ability to replicate.

“With any disease that causes high mortality, the idea isn’t so much to absolutely stop viral replication as to slow it down so that the patient’s immune system can catch up and ultimately eradicate the infection,” Hostetler said.

One of the viruses seemingly impacted by brincidofovir is Ebola, though Hostetler’s focus at the time was elsewhere. Brincidofovir targets double-stranded DNA viruses like herpes, cytomegalovirus, Epstein-Barr, hepatitis and papillomavirus. Ebola is an RNA virus. It replicates differently.

“Brincidofovir is the first broad-spectrum antiviral for DNA viruses. It’s not unprecedented that it might also work against RNA viruses like Ebola, but back then, the greatest interest was in DNA viruses,” he said.

Unable to arouse outside interest and investment in brincidofovir, Hostetler founded Chimerix in Durham, N.C. to further develop the drug – both for smallpox and for other diseases. These efforts have progressed measurably. Phase 3 trials under the Food and Drug Administration’s (FDA) animal rule are planned next year for a smallpox treatment. Phase three human trials are underway for brincidofovir as a therapy for cytomegalovirus and adenovirus – common viruses that can cause fever, diarrhea, conjunctivitis and bladder infections, but in persons with weakened or suppressed immune systems are life-threatening.

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Ebola crisis

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New melanoma drug therapy improves survival rate


Combining Zelboraf with cobimetinib also shows a decreased risk of secondary cancers.

Antoni Ribas, UCLA

A researcher at UCLA’s Jonsson Comprehensive Cancer Center has helped develop a combination drug therapy that shows promise in extending the lives of people with metastatic melanoma. This new therapy also accomplishes this without the side effect of a secondary skin cancer seen in some patients prescribed only one of the drugs.

An estimated 70,000 new cases of melanoma are diagnosed each year in the United States. Of those, 8,000 people will eventually die of the disease, when the cancer spreads to other parts of their bodies. About half the people with this metastatic melanoma, or 4,000 people a year, have a mutated protein called BRAF mutation.

In the new study co-authored by Dr. Antoni Ribas, UCLA professor of medicine and a member of the Jonsson Cancer Center, researchers found that the BRAF mutation gives melanoma the signal to grow continuously as a cancer.

This mutation can be treated with the recently FDA-approved drug Zelboraf. But Zelboraf taken by itself  cannot completely block that signal. The study showed that when the experimental drug cobimetinib is added, the combination slows the growth of the melanoma.

The study was published online by The New England Journal of Medicine, and will appear in its November print edition.

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