TAG: "Drugs"

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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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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Clinical trial launched to evaluate calcium channel blocker for Parkinson’s


Drug used to treat high blood pressure being tested to see if slows progression of Parkinson’s.

Irene Litvan, UC San Diego

Researchers at the UC San Diego School of Medicine have launched a phase three clinical trial to evaluate the drug isradipine, a calcium channel blocker often used to treat high blood pressure, as a potential new treatment for Parkinson disease (PD). The goal of the study is to determine whether the drug can slow the progression of the disease by keeping the brain’s dopamine-producing cells healthier for a longer period of time.

“Isradipine has been demonstrated to be safe and tolerable in patients with Parkinson’s disease,” said Irene Litvan, M.D., site investigator and director of the Movement Disorder Center at UC San Diego Health System. “This new study will determine whether the drug can be effective in slowing the progression of the disease and could, thereby, complement existing symptomatic treatments to improve the quality of life of individuals with the disease.”

PD is a progressive neurological disorder that affects an individual’s speed and amplitude of movements and decreases the speech volume.  Patients with PD experience stiffness or rigidity of the arms and legs and walking difficulties in addition to tremors in their hands, arms, legs or jaw. Patients with PD also experience vivid dreams, depression and constipation.

Isradipine is a Food and Drug Administration-approved drug to treat high blood pressure. Prior population studies have shown that people taking isradipine for high blood pressure have a lower incidence of PD. Additionally, isradipine is in a category of drugs called calcium channel blockers, meaning they inhibit certain cellular functions. Overactive calcium channels may play a role in the death of the dopamine producing cells in the brain that is one of the hallmarks of PD.

A phase two evaluation of isradipine, which was conducted to determine the safety and appropriate dosage for the drug, was completed in 2012. The study was funded by a $2.1 million grant from The Michael J. Fox Foundation for Parkinson’s Research (MJFF), which also supported preclinical research into the effects of isradipine on Parkinson’s progression by D. James Surmeier, Ph.D., of Northwestern University.

The study, called STEADY-PD, is sponsored by the Parkinson Study Group and is co-led by the University of Rochester Medical Center (URMC) and Northwestern University. UC San Diego Health System is one of the national research participants.

Patients who are eligible for the clinical trial will have been diagnosed with PD for less than 3 years and are not currently on any dopaminergic therapy such as levodopa, dopamine agonist, or MAO-B inhibitors.

“If it proves to be effective, this drug will change the way we treat Parkinson’s disease, and the major advantage of it is that isradipine is already widely available, inexpensive and will allow for rapid translation of our research into clinical practice,” said Tanya Simuni, M.D., principal investigator of the study and professor of neurology at Northwestern University Feinberg School of Medicine. “Although we now have very effective symptomatic treatments to manage Parkinson’s, the development of a disease-modifying intervention remains the Holy Grail.”

Patients with PD are advised not to take this medication if they are not part of this therapeutic clinical trial.

For additional information about this clinical trial, please contact the UC San Diego Health System site coordinator at (858) 822-5751 or rellam@ucsd.edu.

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Mining our microbes for drugs


Antibiotic from bacteria in vagina proves value of new approach.

Michael Fischbach, UC San Francisco

Bacteria that normally live in and upon us have genetic blueprints that enable them to make thousands of molecules that act like drugs, and some of these molecules might serve as the basis for new human therapeutics, according to UC San Francisco researchers.

In a study published in today’s (Sept. 11) issue of Cell, the scientists purified and solved the structure of one of the molecules they identified, an antibiotic they named lactocillin, which is made by a common bacterial species, Lactobacillus gasseri, found in the microbial community within the vagina. The antibiotic is closely related to others already being tested clinically by pharmaceutical companies. Lactocillin kills several vaginal bacterial pathogens, but spares species known to harmlessly dwell in the vagina.

This example suggests that there may be an important role for many naturally occurring drugs – made by our own microbes — in maintaining human health, said the senior author of the study, Michael Fischbach, Ph.D., an assistant professor of bioengineering with the UCSF School of Pharmacy, who has established a career discovering interesting molecules made by microbes.

“We used to think that drugs were developed by drug companies, approved by the FDA and prescribed by physicians, but we now think there are many drugs of equal potency and specificity being produced by the human microbiota,” Fischbach said.

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Targeted leukemia treatment shows promise


UC Davis develops unique treatment approach.

Noriko Satake, UC Davis

Noriko Satake, UC Davis pediatric oncologist and researcher, has demonstrated in laboratory studies that a new, targeted treatment for leukemia is effective.

Satake’s research was published Sept. 9 in the British Journal of Haematology.

“We identified a novel molecular target that is important for the growth of precursor B-cell acute lymphoblastic leukemia (ALL), the most common cancer in children,” Satake said. “We developed a unique treatment approach using a drug that blocks the target molecule and kills leukemia cells, a nanoparticle vehicle that carries the drug, and an antibody driver that delivers the nanocomplexes (drug-loaded nanoparticles) to leukemia cells.

“We showed great efficacy of these new drug nanocomplexes on a cell line and on primary leukemia samples,” she added. “We also demonstrated that they had minimal toxicities on normal blood cells.”

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FDA approves new melanoma drug


The drug is a ‘game changer,’ says UCLA’s Dr. Antoni Ribas, the study’s principal investigator.

UCLA's Dr. Antoni Ribas (right) with Tom Stutz, whose health improved dramatically after treatment with the newly approved drug.

The U.S. Food and Drug Administration today (Sept.4) approved a new immunotherapy drug to treat advanced melanoma, signaling a paradigm shift in the way the deadly skin cancer is treated.

The drug, Keytruda, was tested on more than 600 patients who had melanoma that had spread throughout their bodies. Because so many of the patients in the early testing showed significant long-lasting responses, the study was continued and the FDA granted the drug “breakthrough therapy” status, allowing it to be fast-tracked for approval.

The largest phase one study in the history of oncology, the research was conducted at UCLA and 11 other sites in the U.S., Europe and Australia.

Keytruda, formerly known as MK-3475, is an antibody that targets a protein called PD-1 that is expressed by immune cells. The protein puts the immune system’s brakes on, keeping its T cells from recognizing and attacking cancer cells, said Dr. Antoni Ribas, the study’s principal investigator and a professor of medicine in the division of hematology–oncology at the David Geffen School of Medicine at UCLA.

For many years, when using immunotherapy to fight cancer, doctors’ strategy has been to bolster the immune system so it could kill the cancer cells. But the approach had limited success because PD-1 prevented the immune system from becoming active enough to attack the cancer. Keytruda, in effect, cuts the brake lines, freeing up the immune system to attack the cancer.

“This drug is a game changer, a very significant advance in the treatment of melanoma,” said Ribas, who also is a researcher at UCLA’s Jonsson Comprehensive Cancer Center. “For patients who have not responded to prior therapies, this drug now provides a very real chance to shrink their tumors and the hope of a lasting response to treatment.”

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Depression questionnaires could lead to unneeded antidepressant prescriptions


Study highlights need for research to determine how best to apply such questionnaires.

Anthony Jerant examines a patient in the Family & Community Medicine Clinic of UC Davis Health System.

Short questionnaires used to identify patients at risk for depression are linked with antidepressant medications being prescribed when they may not be needed, according to new research from UC Davis Health System to be published in the September-October issue of the Journal of the American Board of Family Medicine.

Known as “brief depression symptom measures,” the self-administered questionnaires are used in primary care settings to determine the frequency and severity of depression symptoms among patients. Several questionnaires have been developed to help reduce untreated depression, a serious mental illness that can jeopardize relationships, employment and quality of life and increase the risks of heart disease, drug abuse and suicide.

The UC Davis team was concerned that the questionnaires might lead to prescriptions for antidepressant medication being given to those who aren’t depressed. Antidepressants are effective in treating moderate-to-severe depression but can have significant side effects, including sexual dysfunction, sedation and anxiety. They also have to be taken over several months to be effective.

“It is important to treat depression, but equally important to make sure those who get treatment actually need it,” said Anthony Jerant, professor of family and community medicine at UC Davis and lead author of the study.

The exploratory study included 595 patients of primary care offices affiliated with Kaiser Permanente in Sacramento, San Francisco VA Medical Center, Sutter Medical Group in Sacramento, UC Davis, UC San Francisco and VA Northern California Healthcare System.

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Aspirin’s second effect


White blood cell research shows how causing, conquering inflammation inextricably linked.

Scanning electron micrograph of macrophage. (Image courtesy of National Cancer Institute).

Hugely popular non-steroidal anti-inflammation drugs like aspirin, naproxen (marketed as Aleve) and ibuprofen (Advil, Motrin) all work by inhibiting or killing an enzyme called cyclooxygenase – a key catalyst in production of hormone-like lipid compounds called prostaglandins that are linked to a variety of ailments, from headaches and arthritis to menstrual cramps and wound sepsis.

In a new paper, published this week in the online early edition of PNAS, researchers at the UC San Diego School of Medicine conclude that aspirin has a second effect: Not only does it kill cyclooxygenase, thus preventing production of the prostaglandins that cause inflammation and pain, it also prompts the enzyme to generate another compound that hastens the end of inflammation, returning the affected cells to homeostatic health.

“Aspirin causes the cyclooxygenase to make a small amount of a related product called 15-HETE,” said senior author Edward A. Dennis, Ph.D., Distinguished Professor of Pharmacology, Chemistry and Biochemistry. “During infection and inflammation, the 15-HETE can be converted by a second enzyme into lipoxin, which is known to help reverse inflammation and cause its resolution – a good thing.”

Specifically, Dennis and colleagues looked at the function of a type of white blood cells called macrophages, a major player in the body’s immune response to injury and infection. They found that macrophages contain the biochemical tools to not just initiate inflammation, a natural part of the immune response, but also to promote recovery from inflammation by releasing 15-HETE and converting it into lipoxin as the inflammation progresses.

Dennis said the findings may open new possibilities for anti-inflammatory therapies by developing new drugs based on analogues of lipoxin and other related molecules that promote resolution of inflammation. “If we can find ways to promote more resolution of inflammation, we can promote health,” he said.

Co-authors include Paul C. Norris, David Gosselin, Donna Reichart and Christopher K. Glass, all at UC San Diego.

Funding support for this research came, in part, from the National Institutes of Health (grants U54 GM069338 and T32 GM007752).

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Grant to fund work to develop new class of drugs for treating breast cancer


UC Santa Cruz’s Seth Rubin receives Breast Cancer Research Program Breakthrough Award.

Seth Rubin, UC Santa Cruz

UC Santa Cruz cancer researcher Seth Rubin has received a $350,000 grant to fund his work toward the development of a new class of drugs for treating breast cancer. The grant is a Breast Cancer Research Program Breakthrough Award from the congressionally directed medical research programs of the U.S. Department of Defense.

Rubin, an associate professor of chemistry and biochemistry, will use the grant to build on his recent discoveries regarding a key tumor suppressor protein that is inactivated in most breast cancer cells. The retinoblastoma tumor suppressor protein (Rb) helps regulate the cycle of cell growth and division, putting the brakes on cell proliferation when it is active. In normal cells, Rb coordinates cellular growth signals, turning on and off to ensure that cells divide at the right time. Genetic changes in cancer cells disrupt this regulatory pathway and allow cells to multiply out of control.

Rubin’s research has revealed important details of the molecular mechanisms involved in turning Rb on and off. These findings suggested the possibility of a new class of therapeutic molecules that target the retinoblastoma protein directly. Most attempts to target the retinoblastoma pathway with drugs have focused on blocking the action of other proteins that inactivate Rb.

“A common analogy is to think of cancer cells as being like a car with a jammed accelerator and broken brakes, so the cells can’t stop proliferating. Most drugs target the jammed accelerator and knock down proteins that are too active. We want to target the broken brakes and restore the tumor suppressor activity,” Rubin said.

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FDA approves cervical cancer treatment based on UC Irvine-led study


Clinical trial found therapy effective in recurrent and metastatic cancer.

The U.S. Food and Drug Administration today (Aug. 14) approved bevacizumab, also known as Avastin, to treat persistent, recurrent or metastatic cervical cancer.

The approval is based on a clinical trial led by UC Irvine Health gynecologic oncologist Dr. Krishnansu S. Tewari and conducted by the Gynecological Oncology Group, now known as NRG Oncology.

The phase three randomized trial enrolled 452 women, including UC Irvine Health patients, and found that combining chemotherapy with bevacizumab extended median survival to 17 months, compared to 13.3 months for those receiving chemotherapy without it. The FDA approval allows its use in combination with paclitaxel and cisplatin or paclitaxel and topotecan.

Treatment with bevacizumab — an anti-angiogenesis agent that inhibits a tumor’s ability to form new blood vessels — caused no significant deterioration in patients’ quality of life, Tewari said. Trial results appeared in the Feb. 20 issue of the New England Journal of Medicine.

“This trial showed for the first time that a targeted agent could improve overall survival in a gynecologic cancer,” said Tewari, a professor of obstetrics & gynecology at UC Irvine. “Women with metastatic or recurrent cervical cancer don’t have many options. Now we finally have a therapy that helps them live longer.”

The findings already have changed U.S. treatment for advanced cervical cancer. Within a month of the study’s presentation at the June 2013 meeting of the American Society of Clinical Oncology, the National Comprehensive Cancer Network listed the cisplatin-paclitaxel-bevacizumab triplet in the NCCN Cervical Cancer Treatment Guidelines Update.

Although a difference of three to seven months may not seem like a long time, Tewari said it is important to understand that this patient population responds very poorly to even one line of therapy and that those minimal responses tend to be short-lived.

“We do not have the luxury of treating women who have advanced cervical cancer with multiple lines of therapy over many years, as we do with more [chemotherapy] sensitive malignancies such as ovarian or breast cancer,” Tewari said. “However, these findings show that we may be on the cusp of converting this disease from a terminal to a chronic condition where the 3.7 months provides a window of opportunity in which patients might benefit from new therapies, including other anti-angiogenesis drugs and immunotherapies that are now being studied.”

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Antimalarial drug shipped to Africa


Project begun by Berkeley Lab’s Jay Keasling to benefit millions of people.

Jay Keasling with children in a village outside Nairobi, Kenya. (Photo by Gabrielle Tenenbaum)

A project begun some 13 years ago by Jay Keasling, the associate laboratory director for biosciences at Berkeley Lab and the CEO of the Joint BioEnergy Institute (JBEI), was culminated with an announcement on Aug. 12 from the partnership of Sanofi, the multinational pharmaceutical company, and PATH, the nonprofit global health organization. Sanofi/PATH announced the shipment of 1.7 million treatments of semi-synthetic artemisinin to malaria-endemic countries in Africa. Unlike conventional artemisinin, which is derived from the bark of the sweet wormwood plant, this synthetic version of the World Health Organization’s frontline antimalarial drug is derived from yeast. The addition of a microbial-based source of artemisinin to the botanical source provides a stable new option for treating the millions of victims who are stricken with malaria each year, most of them children.

Sanofi has produced enough of the drug for 70 million treatments, and has the capacity to produce up to 150 million treatments annually. It was Keasling and his research group, using the tools of synthetic biology, who engineered the genes and metabolic pathways that enabled first E. coli and later yeast to produce artemisinic acid, the precursor to artemisin. This led to a $42.6 million grant from the Bill and Melinda Gates Foundation for further basic research that ultimately led to yesterday’s announcement by Sanofi/PATH. Keasling, who is also the Hubbard Howe Jr. Distinguished Professor in Biochemical Engineering at UC Berkeley, among other titles, has been recognized for leading this groundbreaking research with numerous awards including the Biotechnology Industry Organization’s first Biotech Humanitarian Award.

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