BreakThrough Digest Medical News |
- Cancer’s next magic bullet may be magic shotgun
- U of M researchers find natural antioxidant can protect against cardiovascular disease
- Nanoparticles engineered at Notre Dame promise to improve blood cancer treatment
| Cancer’s next magic bullet may be magic shotgun Posted: 14 Jun 2012 09:00 PM PDT
A new approach to drug design, pioneered by a group of researchers at the University of California, San Francisco (UCSF) and Mt. Sinai, New York, promises to help identify future drugs to fight cancer and other diseases that will be more effective and have fewer side effects.
Rather than seeking to find magic bullets?chemicals that specifically attack one gene or protein involved in one particular part of a disease process?the new approach looks to find “magic shotguns” by sifting through the known universe of chemicals to find the few special molecules that broadly disrupt the whole diseases process. “We’ve always been looking for magic bullets,” said Kevan Shokat, PhD, a Howard Hughes Medical Institute Investigator and the Chair of the Department of Cellular and Molecular Pharmacology at UCSF. “This is a magic shotgun?it doesn’t inhibit one target but a set of targets?and that gives us a much, much better ability to stop the cancer without causing as many side effects.” Described in the June 7, 2012 issue of the journal Nature, the magic shotgun approach has already yielded two potential drugs, called AD80 and AD81, which in fruit flies were more effective and less toxic than the drug vandetanib, which was approved by the U.S. Food & Drug Administration last year for the treatment of a certain type of thyroid cancer. Expanding the Targets to Lower a Drug’s Toxicity
Drug design is basically all about disruption. In any disease, there are numerous molecular interactions and other processes that take place within specific tissues, and in the broadest sense, most drugs are simply chemicals that interfere with the proteins and genes involved in those processes. The better a drug disrupts key parts of a disease process, the more effective it is. The toxicity of a drug, on the other hand, refers to how it also disrupts other parts of the body’s system. Drugs always fall short of perfection in this sense, and all pharmaceuticals have some level of toxicity due to unwanted interactions the drugs have with other molecules in the body. Scientists use something called the therapeutic index (the ratio of effective dose to toxic dose) as a way of defining how severe the side effects of a given drug would be. Many of the safest drugs on the market have therapeutic indexes that are 20 or higher?meaning that you would have to take 20 times the prescribed dose to suffer severe side effects. Many cancer drugs, on the other hand, have a therapeutic index of 1. In other words, the amount of the drug you need to take to treat the cancer is the exact amount that causes severe side effects. The problem, said Shokat, comes down to the fact that cancer drug targets are so similar to normal human proteins that the drugs have widespread effects felt far outside the tumor. While suffering the side effects of drugs is a reality that many people with cancer bravely face, finding ways of minimizing this toxicity is a big goal pharmaceutical companies would like to solve. Shokat and his colleagues believe the shotgun approach is one way to do this. The dogma that the best drugs are the most selective could be wrong, he said, and for cancer a magic shotgun may be more effective than a magic bullet. Looking at fruit flies, they found a way to screen compounds to find the few that best disrupt an entire network of interacting genes and proteins. Rather than judging a compound according to how well it inhibits a specific target, they judged as best the compounds that inhibited not only that specific target but disrupted other parts of the network while not interacting with other genes and proteins that would cause toxic side effects. ### The article, “Chemical genetic discovery of targets and anti-targets for cancer polypharmacology” by Arvin C. Dar, Tirtha K. Das, Kevan M. Shokat and Ross Cagan appears in the June 7, 2012 issue of the journal Nature. See: http://dx.doi.org/10.1038/nature11127 This work was supported by the American Cancer Society, The Waxman Foundation, and the National Institutes of Health?through grants R01CA109730, R01CA084309, R01EB001987 and P01 CA081403-11. UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. Follow UCSF
Contact: Jason Socrates Bardi |
| U of M researchers find natural antioxidant can protect against cardiovascular disease Posted: 14 Jun 2012 09:00 PM PDT University of Minnesota Medical School researchers have collaborated with the School of Public Health and discovered an enzyme that, when found at high levels and alongside low levels of HDL (good cholesterol), can dramatically reduce the risk of cardiovascular disease.
The enzyme ? glutathione peroxidase, or GPx3 ? is a natural antioxidant that helps protect organisms from oxidant injury and helps the body naturally repair itself. Researchers have found that patients with high levels of good cholesterol, the GPx3 enzyme does not make a significant difference. However, those patients with low levels of good cholesterol, the GPx3 enzyme could potentially be a big benefit. The enzyme’s link to cardiovascular disease may also help determine cardiovascular risk in patients with low levels of good cholesterol and low levels of the protective GPx3. The new research, published today by PLoS One, supports the view that natural antioxidants may offer the human body profound benefits. “In our study, we found that people with high levels of the GPx3 enzyme and low levels of good cholesterol were six times less likely to develop cardiovascular disease than people with low levels of both,” said lead author Jordan L. Holtzman, M.D., Ph.D., professor of pharmacology and medicine within the University of Minnesota Medical School. “This GPx3 enzyme gives us a good reason to believe that natural antioxidants like GPx3 are good for heart health.” The combination of low HDL and low GPx3 affects an estimated 50 million people ? one in four adults ? in the U.S. This condition can lead to fatal heart attacks and strokes. Researchers continue to look for new ways to better predict who is at risk for these diseases and how patients can limit the impact of the disease once it’s diagnosed. “It’s important to point out that people should not rush out to their doctors and demand testing for the GPx3 enzyme,” said Holtzman. “But in time, we hope that measuring this enzyme will be a common blood test when determining whether a patient is at risk for cardiovascular disease, including heart attacks and strokes.” To arrive at his results, Holtzman and his colleagues studied the three major risk factors for cardiovascular disease: hypertension, smoking and high cholesterol. Data suggests that those with low levels of HDL and GPx3 were six times more likely to die from cardiovascular disease, including heart attack or stroke, than those with low levels of HDL and high levels of GPx3. The study examined 130 stored samples from the Minnesota Heart Survey from participants who died of cardiovascular disease after 5-12 years of follow-up care. The ages of patients studied ranged from 26-85 years old. Their data was compared to 240 control samples. “This is an important enzyme for people with low HDL cholesterol,” said Holtzman. “We think further research will be important in determining the future role of GPx3 and what drugs may serve to increase its activity in the blood.” ### The research reported in this publication was supported by the National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (RO1-HL23727), the Mayo Chair Endowment, School of Public Health, University of Minnesota (DJ), and grant no. 2005R013 from the Netherlands Heart Foundation, Den Haag, the Netherlands (BB). About the Medical School: The University of Minnesota Medical School, with its two campuses in the Twin Cities and Duluth, is a leading educator of the next generation of physicians. Our graduates and the school’s 3,800 faculty physicians and scientists advance patient care, discover biomedical research breakthroughs with more than $180 million in sponsored research annually, and enhance health through world-class patient care for the state of Minnesota and beyond. Visit www.med.umn.edu to learn more. Contact: Matt DePoint |
| Nanoparticles engineered at Notre Dame promise to improve blood cancer treatment Posted: 14 Jun 2012 09:00 PM PDT Researchers from the University of Notre Dame have engineered nanoparticles that show great promise for the treatment of multiple myeloma (MM), an incurable cancer of the plasma cells in bone marrow.
One of the difficulties doctors face in treating MM comes from the fact that cancer cells of this type start to develop resistance to the leading chemotherapeutic treatment, doxorubicin, when they adhere to tissue in bone marrow. “The nanoparticles we have designed accomplish many things at once,” says Ba?ar Bilgiçer, assistant professor of chemical and biomolecular engineering and chemistry and biochemistry, and an investigator in Notre Dame’s Advanced Diagnostics and Therapeutics (AD&T) initiative. “First, they reduce the development of resistance to doxorubicin. Second, they actually get the cancer cells to actively consume the drug-loaded nanoparticles. Third, they reduce the toxic effect the drug has on healthy organs.” A sequence of images showing multiple myeloma cells internalizing the engineered nanoparticles The nanoparticles are coated with a special peptide that targets a specific receptor on the outside of multiple myeloma cells. These receptors cause the cells to adhere to bone marrow tissue and turn on the drug resistance mechanisms. But through the use of the newly developed peptide, the nanoparticles are able to bind to the receptors instead and prevent the cancer cells from adhering to the bone marrow in the first place. The particles also carry the chemotherapeutic drug with them. When a particle attaches itself to an MM cell, the cell rapidly takes up the nanoparticle, and only then is the drug released, causing the DNA of cancer cell to break apart and the cell to die. “Our research on mice shows that the nanoparticle formulation reduces the toxic effect doxorubicin has on other tissues, such as the kidneys and liver,” adds Tanyel Kiziltepe, a research assistant professor with the Department of Chemical and Biomolecular Engineering and AD&T. “We believe further research will show that the heart is less affected as well. This could greatly reduce the harmful side-effects of this chemotherapy.” The group had to tackle three important problems associated with all nanoparticle-based therapies, explains Jonathan Ashley, one of the leading researchers of the project. “There was some complex bioengineering involved in developing the particles. We were able to precisely control the number of drug and targeting elements on each nanoparticle, achieve homogeneous nanoparticle size distribution and eliminate the batch-to-batch variability in particle production.” Before advancing to human clinical trials, the team plans further research and testing to improve the design of the nanoparticles and to find the optimum amount and combination of chemotherapy drugs for this new treatment. The research is described in greater detail in a recent edition of Nature’s Blood Cancer Journal. It was supported by funding from the Indiana Clinical and Translational Sciences Institute. Contact: Ba?ar Bilgiçer |
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