BreakThrough Digest Medical News |
- NIH scientists map first steps in flu antibody development
- Scientist creates new cancer drug that is 10 times more potent
- Study pinpoints malignant mesothelioma patients likely to benefit from drug pemetrexed
| NIH scientists map first steps in flu antibody development Posted: 28 Aug 2012 09:00 PM PDT National Institutes of Health scientists have identified how a kind of immature immune cell responds to a part of influenza virus and have traced the path those cells take to generate antibodies that can neutralize a wide range of influenza virus strains. Study researchers from the National Institute of Allergy and Infectious Diseases (NIAID), part of NIH, were led by Gary Nabel, M.D., Ph.D., director of NIAID’s Vaccine Research Center. Their findings appear online in advance of print in Nature.
“This new understanding of how an immature immune cell transforms into a mature B cell capable of producing antibodies that neutralize a wide variety of influenza viruses could speed progress toward a universal flu vaccine?one that would provide protection against most or all influenza virus strains,” said NIAID Director Anthony S. Fauci, M.D. Universal flu vaccines, which are in development at NIAID and elsewhere, differ significantly from standard influenza vaccines. Unlike standard vaccines, which prompt the immune system to make antibodies aimed at the variable head of a lollipop-shaped influenza protein called hemagglutinin (HA), a universal flu vaccine would elicit antibodies that target HA’s stem. Because the stem varies relatively little from strain to strain and does not change substantially from year to year, a vaccine that can elicit HA stem-targeted antibodies would, in theory, provide recipients with broad protection from the flu. The neutralizing antibodies generated would recognize any strain of flu virus. Finding ways to elicit these broadly neutralizing antibodies (bnAbs) is thus a key challenge for universal flu vaccine developers. However, there is a snag. Researchers knew what the end products (mature bnAbs) look like, but they did not have a clear picture of the initial steps that stimulate their development. Specifically, they lacked an understanding of how the precursor immune cell?called a naive B cell?first recognizes the HA stem and starts down a path that ends in mature bnAb-producing B cells. In the new research, Dr. Nabel and his colleagues demonstrated that the immature antibodies can only recognize and bind to HA’s stem when the antibodies are attached to the membrane of a naive B cell. The investigators showed that this initial contact delivers a signal that triggers the maturation of these naive B cell into countless daughter cells, some of which acquire the specific genetic changes that give rise to HA-stem-binding antibodies. “We have repeated the first critical steps in the route leading to broadly neutralizing influenza antibodies,” said Dr. Nabel. “Understanding how such antibodies originate could allow for rational design of vaccine candidates that would prompt the correct naive B cells to go on to mature into bnAb-producing cells.” The findings could also be relevant to HIV vaccine design, noted Dr. Nabel. There, too, eliciting bnAbs to relatively constant portions of HIV is a key goal. The insights into how naive B cells recognize constant components of a virus and mature into bnAb-producing cells could guide efforts to design an HIV vaccine capable of reproducing this effect. ### NIAID conducts and supports research?at NIH, throughout the United States, and worldwide?to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID website at http://www.niaid.nih.gov. About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit http://www.nih.gov. NIH…Turning Discovery Into Health Reference: D Lingwood et al. Structural and genetic basis for development of broadly neutralizing influenza antibodies. Nature DOI 10.1038/nature11371 (2012). Contact: NIAID Office of Communications |
| Scientist creates new cancer drug that is 10 times more potent Posted: 28 Aug 2012 09:00 PM PDT
Legend has it that Ralph Waldo Emerson once said, “Build a better mousetrap, and the world will beat a path to your door.” University of Missouri researchers are doing just that, but instead of building mousetraps, the scientists are targeting cancer drugs. In a new study, MU medicinal chemists have taken an existing drug that is being developed for use in fighting certain types of cancer, added a special structure to it, and created a more potent, efficient weapon against cancer.
“Over the past decade, we have seen an increasing interest in using carboranes in drug design,” said Mark W. Lee Jr., assistant professor of chemistry in College of Arts and Science. “Carboranes are clusters of three elements ? boron, carbon and hydrogen. Carboranes don’t fight cancer directly, but they aid in the ability of a drug to bind more tightly to its target, creating a more potent mechanism for destroying the cancer cells.” In the study, Lee and his research team used carboranes to build new drugs designed to shut off a cancer cell’s energy production, which is vital for the cell’s survival. All cells produce energy through complex, multi-step processes. The key to an effective drug is targeting the process that cancer cells depend on more than healthy cells. By increasing the binding strength of a drug, a smaller dose is required, minimizing side effects and increasing the effectiveness of the therapy. With carboranes, Lee found that the drug is able to bind 10 times more powerfully. “The reason why these drugs bind stronger to their target is because carboranes exploit a unique and very strong form of hydrogen bonding, the strongest form of interactions for drugs,” Lee said. Lee said that this discovery also will lead to further uses for the drug. “Too often, after radiation or chemotherapy, cancer cells repair themselves and reinvade the body,” Lee said. “This drug not only selectively shuts off the energy production for the cancer cells, but it also inhibits the processes that allow those cancer cells to repair themselves. When we tested our carborane-based drugs, we found that they were unimaginably potent. So far, we have tested this on breast, lung and colon cancer, all with exceptional results.” According to Lee, this is the first study to show systematically how carboranes can improve the activity of a drug. Lee believes this discovery will open additional possibilities of improving drugs that are used to treat other diseases, not just cancer. “The end result is that these new drugs could be many thousands of times more potent than the drugs that are used in the clinics today,” Lee said. While it will be several years before the new drug would be available on the market, Lee said that clinical trials could begin within the next two years. Additionally, further testing on other types of cancer is underway. The study was published in the Journal of Medicinal Chemistry, a publication of the American Chemical Society. Contact: Christian Basi |
| Study pinpoints malignant mesothelioma patients likely to benefit from drug pemetrexed Posted: 28 Aug 2012 09:00 PM PDT
Previous studies have hypothesized that low levels of the enzyme thymidylate synthase (TS) likely mark patients who will benefit from the drug pemetrexed ? but results have been inconclusive at best and at times contradictory. A University of Colorado Cancer Center study recently published in the Journal of Thoracic Oncology provides an explanation why: only in combination with high levels of a second enzyme, FPGS, does low TS predict response to pemetrexed in patients with malignant pleural mesothelioma.
“The hope is that oncologists could test a patient for TS and FPGS levels and so discover if the patient should be treated with pemetrexed or if another therapy might be more appropriate,” says the paper’s first author, Daniel C. Christoph, MD, PhD, medical oncologist at the West German Cancer Center, working as an international postdoctoral researcher in the lab of CU Cancer Center investigator, Fred Hirsch, MD, PhD. Pemetrexed works by inhibiting the enzyme TS, which cancer cells need in order to replicate their DNA. So it stands to reason that tumors already low in TS would be most affected by the drug ? blocking the remaining TS would effectively stop the ability of cancer cells to synthesize new DNA. However, Christoph and colleagues tested 84 samples of mesothelioma in which patients had been treated with pemetrexed and found that low levels of TS only in combination with concurrently high levels of FPGS predicted patients’ response to the drug. The study also explained the mechanism by which FPGS increases the clinical effectiveness of pemetrexed: “High levels of FPGS allow pemetrexed to stay longer inside cells, giving the drug longer to work against TS,” Christoph says. Of the samples tested, patients with low TS and high FPGS had more response to pemetrexed and longer durations of survival. According to Christoph, the current study provides the preclinical work needed to justify exploring the predictive power of TS and FPGS in mesothelioma patients. A prospective observational study of these biomarkers could lead to their wide use in predicting patients’ response to pemetrexed. Contact: Garth Sundem |
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