TAG: "Drugs"

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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Bone drugs may not protect women from breast cancer


New analysis of clinical trial data suggests earlier evidence was misleading.

Trisha Hue, UC San Francisco

Osteoporosis drugs known as bisphosphonates may not protect women from breast cancer as had been thought, according to a new study led by researchers at UC San Francisco.

The drugs’ protective effect was widely assumed after several observational studies showed that women who took them were less likely to get breast cancer.

But when researchers assessed the effect of two of the most widely used osteoporosis drugs – sold under the brand names, Fosamax and Reclast – in two large randomized clinical trials, neither drug protected women with osteoporosis from getting breast cancer. The results were published today (Aug. 11) in JAMA Internal Medicine.

The researchers said the link found in the previous observational studies between taking the drugs and having a lower incidence of breast cancer may be due to a third factor, low estrogen.

Since having low estrogen both weakens bones and protects against most breast cancers, the women most likely to be prescribed drugs for osteoporosis are usually also at lower risk for breast cancer.

“They may have seen a lower risk of breast cancer in women using bisphosphonates in the earlier observational studies because those women had a lower risk of breast cancer to begin with,” said Trisha Hue, Ph.D., lead author of the study.

“Post-menopausal women with osteoporosis usually have low estrogen levels,” said Hue, an epidemiologist with the San Francisco Coordinating Center, a partnership between the CPMC Research Institute and the UCSF Department of Epidemiology & Biostatistics. “Lower levels of estrogen are strongly associated with a lower risk of breast cancer.”

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Researchers discover how a drug specifically kills cancer cells


Finding culminates nearly a decade of research into the role of arginine.

Hsing-Jien Kung

Researchers at UC Davis, City of Hope, Taipai Medical University and National Health Research Institutes in Taiwan have discovered how a drug that deprives the cells of a key amino acid specifically kills cancer cells.

Their paper, published today (Aug. 11) in Proceedings of the Academy of Sciences, is the culmination of nearly a decade of research into the role of arginine – and its deprivation – in the generation of excessive autophagy, a process in which the cell dies by eating itself.

Study co-author Hsing-Jien Kung, a renowned cancer biologist and UC Davis professor emeritus who now leads the National Health Research Institutes in Taipei, Taiwan, first discovered the mechanism by which arginine deprivation works in 2009, when he led basic science research at the UC Davis Comprehensive Cancer Center.

“Traditional cancer therapies involve ‘poisoning’ by toxic chemicals or ‘burning’ by radiation cancer cells to death, which often have side effects,” Kung said. “An emerging strategy is to ‘starve’ cancer cells to death, taking advantage of the different metabolic requirements of normal and cancer cells. This approach is generally milder, but as this study illustrates, it also utilizes a different death mechanism, which may complement the killing effects of the conventional therapy.”

The discovery led to the further development of a drug now being tested in several clinical trials against melanoma, prostate, liver, sarcoma and other cancers that lack an enzyme that helps synthesize arginine, an amino acid with an essential role in cell division, immune function and hormone regulation.

The study published today describes how arginine starvation specifically kills tumor cells by a novel mechanism involving mitochondria dysfunction, reactive oxygen species generation, nuclear DNA leakage and chromatin autophagy, where leaked DNA is captured and “eaten” by giant autophagosomes.

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How breast cancer usurps powers of mammary stem cells


Finding provides insight into how aggressive breast cancer might be treated.

Mammary cells found during pregnancy that express integrin beta3 (CD61) act as stem cells, capable of reconstituting a new mammary gland in mice. This property may be to blame for the more aggressive nature of beta3-expressing breast cancer cells. Shown is a section from a mammary “outgrowth” harvested at lactation and immuno-stained for the epithelial markers E-cadherin (brown) and alpha-SMA (red).

During pregnancy, certain hormones trigger specialized mammary stem cells to create milk-producing cells essential to lactation. Scientists at the UC San Diego School of Medicine and Moores Cancer Center have found that mammary stem cells associated with the pregnant mammary gland are related to stem cells found in breast cancer.

Writing in today’s (Aug. 11) issue of Developmental Cell, David A. Cheresh, Ph.D., Distinguished Professor of Pathology and vice chair for research and development, Jay Desgrosellier, Ph.D., assistant professor of pathology and colleagues specifically identified a key molecular pathway associated with aggressive breast cancers that is also required for mammary stem cells to promote lactation development during pregnancy.

“By understanding a fundamental mechanism of mammary gland development during pregnancy, we have gained a rare insight into how aggressive breast cancer might be treated,” said Cheresh. “This pathway can be exploited. Certain drugs are known to disrupt this pathway and may interfere with the process of breast cancer progression.”

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Grant awarded to test ‘smart’ chemotherapy drug for bladder cancer


Clinical trial may improve survival rates, transform the standard of care.

Chong-Xian Pan, UC Davis

UC Davis Comprehensive Cancer Center oncologist Chong-Xian Pan has received a $650,000 grant from the VA Northern California Health Care System to conduct the first clinical trial of a novel chemotherapy-delivery drug he developed for bladder cancer patients.

Bladder cancer is one of the 10 most common cancers in the United Sates, however, there has been very little improvement in treatment outcomes during the past three decades said Pan, a genitourologist, the study’s principal investigator, and  leader of the Urothelial Carcinoma Initiative at the Comprehensive Cancer Center.

The researchers hope the trial will result in a more effective therapy and improved treatment outcomes and possibly a cure for bladder cancer.

Standard treatment for non-muscle invasive bladder cancer, which accounts for 80 percent of cases, currently is “intravesical therapy,” which involves a transurethral resection of bladder tumor, a procedure in which a scope is inserted into the patient’s bladder through the urethra and the cancerous cells are removed with a cutting tool.  Most patients then are given a vaccine commonly used to prevent tuberculosis, which stimulates immune cells that can kill bladder cancer cells.

“And that is not good enough,” said Pan, associate professor in the UC Davis Division of Hematology and Oncology.

In 60 percent of cases the cancer returns within two years, Pan said. When it does, oncologists reach for valrubicin, the only Food and Drug Administration-approved drug for recurrent bladder cancer. But valrubicin only works 20 percent of the time.

So Pan and Kit Lam, study co-investigator and chair of the UC Davis Department of Biochemistry and Molecular Medicine, developed a micelle that targets bladder cancer cells and loads them with Paclitaxel, a chemotherapy agent commonly used to treat bladder cancer. The micelle is coated with a PLZ4 ligand, developed by Lam and Pan. Together the ligand-coated micelle enhances Paclitaxel’s effectiveness while decreasing its toxicity.

“It’s like a guided missile,” Pan said.

“Without creating much toxicity, the cancer-targeting micelle has proven effective in killing human bladder cancer cells when injected into a mouse model,” he said. “The goal is to now determine the drug’s safety and effectiveness in humans.”

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