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| 605 | NCATS Screening Technologies Enable Identification of Potential Treatment Target for Neurological Disorder | Improving scientific methods and tools is a key part of the NCATS approach to solving translational problems on a system-wide level, with the goal of delivering more treatments to more patients more quickly. A recent advance in this area — made possible through a project collaboration involving NCATS experts, academic researchers, a patient advocacy group and a pharmaceutical company — already has enabled a research team to identify a potential drug target for an inherited neurological disorder called Charcot-Marie-Tooth disease (CMT). The disease affects the peripheral nerves (i.e., the nerves outside the brain and spinal cord), and individuals with the CMT1A subtype, which affects approximately 1 in 2,500 people in the United States, experience progressive muscle weakness, movement problems, chronic pain and fatigue. The CMT project involved the first combined use of a new type of assay (test) along with a version of high-throughput screening (HTS) developed at NCATS, called quantitative HTS (qHTS), to identify CMT1A therapeutic candidates. In qHTS, researchers use robotics to quickly conduct millions of chemical tests at multiple concentrations to identify compounds with therapeutic potential. Screening at multiple concentrations increases the probability of finding compounds with active pharmacology. James Inglese, Ph.D., director of the NCATS Assay Development and Screening Technology Laboratory, and John Svaren, Ph.D., professor of comparative biosciences at the University of Wisconsin–Madison Waisman Center, led the work with funding from NCATS, the CMT Association (CMTA), the National Institute of Neurological Disorders and Stroke, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The group’s work was published in the September 2014 issue of ACS Chemical Biology. The scientists were looking for agents that could reduce the activity of the gene PMP22, which is over-expressed in patients with CMT1A. To create an assay for this screen, the team, including CMTA-supported postdoctoral fellow Sung-Wook Jang, Ph.D., used a technique called genome editing to insert biological tools known as “reporter” genes directly into the DNA sequence of PMP22 in cells grown in culture. The reporter genes then produced detectable signals — in this case, light — when PMP22 was expressed. This newly developed assay differs from previous versions in an important way. In earlier assays, scientists attached a reporter to a piece of the gene of interest that helps control its expression and then inserted the pair randomly into a cell’s DNA. In contrast, the new assay used targeted integration, meaning the group placed the reporter directly within the sequence of the gene of interest, making the reporter assay more sensitive to a wider range of mechanisms regulating gene expression and, thus, more biologically relevant. Targeted integration of reporter genes provides more assurance that a screen can identify more potential compounds that affect the expression of the gene under study. Inglese, Svaren and colleagues showed that compared with the previous version of the assay, a screen using the new assay produced an expanded list of compounds that decreased PMP22 expression. One of those compounds reduced the gene’s activity through a previously unrecognized mechanism, known as the protein kinase C (PKC) pathway. This finding could spur further exploration of the PKC pathway as a target for potential therapies. Notably, these results also validate the combined use of the targeted integration reporter assay with qHTS, which now can be used in future drug discovery efforts. “In close collaboration with Dr. Inglese’s group at NCATS, we’ve developed an assay that is suitable for screening even larger chemical libraries in pursuit of novel CMTA treatment targets,” Svaren said. CMT patients will not be the only ones to benefit. “This work is a key proof-of-principle and provides a template for drug screens for other types of disorders,” Inglese said. According to the NCATS “3-Ds” philosophy, the team has developed a new approach and demonstrated its potential for improving the search for drug targets, with CMTA as the test case. Now, the group is disseminating this innovative tool to the broader scientific community. The scientists and CMTA have partnered with pharmaceutical company Sanofi-Genzyme to provide the new assay for screens of compound libraries that include more than 2 million small molecules. CMTA will pursue further testing of promising candidates that emerge from these screens and those conducted at NCATS, validating them in animal models and refining them for eventual studies in humans. The team’s collaborative effort to create a state-of-the-art tool for drug discovery embodies the NCATS mission to develop innovative approaches that make translational science more efficient and accelerate the drug development process. Posted November 2014 | ||||||||
| 604 | BrIDGs Scientific Capabilities | BrIDGs offers state-of-the-art expertise and resources for preclinical development.BrIDGs is not a grant program. Instead, BrIDGs provides expertise and resources to further preclinical drug development.Instead of receiving grant funds, selected researchers work with NCATS intramural drug development experts. These partners use the federal government’s contract resources and assistance with establishing and implementing product development plans to produce enough data for an Investigational New Drug (IND) application to a regulatory agency, such as the U.S. Food and Drug Administration. BrIDGs ExpertiseBrIDGs scientists bring decades of experience in industry and academic drug development to each project. Partners tap into staff expertise in process chemistry, formulations development, pharmacokinetics and toxicology. These scientific insights are combined with a thorough understanding of regulatory guidelines, which allows the program to assist with establishing and implementing successful product development plans for IND applications.Completed and active projects include small molecules, peptides, gene therapies and recombinant proteins delivered by oral, topical and injectable routes of administration.BrIDGs ResourcesThrough the BrIDGs program, researchers work with NCATS scientists to produce preclinical data as well as research and clinical material. Data and material are produced by NIH contractors under the direction of NCATS intramural researchers who have expertise in the following development areas:• Synthetic process development• Scale-up and manufacturing of active pharmaceutical ingredients• Development of analytical methods• Development of suitable formulations• Pharmacokinetic/ADME (absorption, distribution, metabolism and excretion) studies, including bioanalytical method transfer and validation• Range-finding initial toxicology studies• IND-directed toxicology studies• Creation of clinical trial supplies• Product development planning and advice in IND preparationBrIDGs partnerships are completed using the contract resources of NCATS and the National Cancer Institute. | ||||||||
| 603 | CTSA Training Enables Research on the Effects of Antibiotics on Body Fat | A core component of NCATS’ Clinical and Translational Science Awards (CTSA) program is training, cultivating and sustaining future leaders in the biomedical research workforce. New York University (NYU) School of Medicine’s Ilseung Cho, M.D., M.S., attests that his school’s CTSA support has made crucial and ongoing contributions to his professional growth and achievements. Cho began studying how antibiotics alter the community of bacteria living in the guts of mice as part of his thesis for a CTSA-funded master’s degree in clinical investigation, a program open to researchers who have completed residency training in a clinical department at NYU. The research, which began during Cho’s last year of his gastroenterology fellowship, has continued through his transition into a faculty member at NYU. Researchers have long known that feeding low doses of antibiotics to farm animals makes them grow faster and up to 15 percent larger, but the mechanism behind the effects has remained unclear. Now, thanks to a study supported by a CTSA training grant and by the NYU Clinical and Translational Science Institute (CTSI), Cho and his colleagues have shed light on several of the changes that occur in those animals. Their success hinged on the connections and ideas generated in the setting of mentoring meetings as part of the CTSA training program. As explained in the August 30, 2012, issue of Nature, the researchers tested low doses of antibiotics in mice to learn about the effects on the animals’ growth and metabolism. Early in the planning for the project, Cho and his mentor, Martin Blaser, M.D., met with several researchers from the NYU CTSI. During the meeting, one of the senior faculty suggested using dual energy X-ray absorptiometry (DEXA) scanning to gauge the animals’ body composition (proportions of fat and lean body mass). The researchers found that although the antibiotic-fed mice weighed the same as the controls (mice not given antibiotics), they had significantly more body fat than control mice. “We didn’t even consider DEXA scanning until NYU CTSI Director Bruce Cronstein, M.D., introduced us to it,” Cho said. “It was serendipity, having the right mentors and the right resources available to you when you need them.” Without the DEXA machine, Cho would not have been able to see the key finding about the body composition of mice that were fed antibiotics. “That was a seminal moment for the research,” Cho explained. It turns out that both sets of mice (those getting antibiotics and the controls) had similar numbers — but different types — of microbes in their guts. The microbes in the antibiotic-fed mice transformed food into a form that is more available to the mouse’s digestive system and altered liver metabolism to favor accumulation of body fat. The study’s findings could have implications for human health. Giving antibiotics to infants might have long-term effects on their metabolism and body composition. More studies are needed to see if shifts in the gut microbiome caused by antibiotics could increase the risk of obesity later in life. Through the CTSA, the researchers got important advice and training that guided the direction of Cho’s research and enabled discovery of the key finding from the study. The work also was supported by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases, the Diane Belfer Program in Human Microbial Ecology, the Philip and Janice Levin Foundation, the Michael Saperstein Fellowship, the J. Craig Venter Institute, and the NYU Genome Technology Center. Cho is continuing his research on antibiotics and the gut ecosystem and still using CTSA resources to accomplish his research goals. He is studying whether giving higher doses of antibiotics for shorter lengths of time — similar to the dosing often used to treat human disease — has the same effect on metabolism. In the long term, he’d like to understand how changes in the gut microbial ecosystem affect diseases he sees in his practice as a gastroenterologist, such as colorectal cancer and inflammatory bowel disease. He now receives further CTSA support via a KL2 award, a program for ongoing training in translational research. “The CTSA provides connections to a broad and varied community of researchers and resources,” he said. “It’s really catapulted my career.” What’s more, Cho is “paying it forward.” As he has advanced in his career, he has engaged more and more students on his research team, and the CTSA’s Mentor Development Program has helped him learn how to be an effective mentor and team leader. And that’s key, according to Michael Pillinger, M.D., director of NYU’s CTSA education core: “The programs that the NIH so generously supports here are not only helping individuals, but also they are clearly helping us build a culture where those individuals help each other to succeed.” Posted December 2012 | ||||||||
| 601 | A New Method to Help Scientists Better Identify Drug Candidates | In the past few years, researchers have discovered that the use of reporter genes, a powerful technique widely used in drug discovery screening, can produce misleading results and lead to wasted effort and inefficiency in the drug discovery process. Now, researchers from NIH’s National Center for Advancing Translational Sciences (NCATS) have designed a novel method that increases the odds of identifying candidate compounds with true activity against biological or disease targets. Scientists use these compounds as molecular tools to understand disease and as starting points for developing new therapeutics. Details of the methodology are described in a correspondence published in the October issue of Nature Methods. A Powerful Technique Reporter genes produce proteins that act as light-generating (e.g., luminescent or fluorescent) sentinels when a chemical compound produces an effect in a testing system (an “assay”) designed to represent a biological or disease process. Such assays enable researchers to examine hundreds of thousands of compounds using robotic high-throughput screening systems, such as those in the NCATS Division of Preclinical Innovation (DPI). Typically, scientists use a single reporter gene for screening; however, because chemical compounds may interact with the reporter gene proteins themselves, rather than with the intended target, these tests can be misleading. Compounds affecting the reporter may inhibit its activity, or alternatively may bind to and stabilize it, increasing its abundance and activity in the cell. In either case, a researcher may see a strong effect of the compound in the assay, and erroneously conclude that this indicates action on the biological pathway or target of interest. But, it is more a case of the reporter doing “false advertising,” leading the researcher to conduct further testing and development, and even clinical trials, that ultimately fail since the compound only has activity on the reporter, not the disease target. “The mission of NCATS is to develop, demonstrate, and disseminate technologies and paradigms that improve the accuracy, efficiency and predictability of the translational process,” said Christopher P. Austin, M.D., NCATS director. “This innovative reporter gene system is a great example of such a platform technology, which will enable researchers worldwide in achieving more reliable results early in the translational process, and avoiding failure at later stages.” A Method Made Better The new method uses two co-expressed reporter genes rather than one. DPI researcher James Inglese, Ph.D., and his postdoctoral fellow Ken C-C Cheng, Ph.D., designed the new method, calling it a “coincidence reporter-gene system for high-throughput screening.” When contemplating the creation of the method, they knew they could not control compounds from interacting with reporters or predict in what situation it may occur. To overcome this, the new method uses a short DNA sequence specially designed to allow the equal expression and proper function of two mechanistically unrelated reporters in the same cell to search for coinciding signals in high-throughput drug screens. For academic researchers who rely on reporter-genes, adding an additional reporter is easy to do, and the plasmids to enable this new method are available through the not-for-profit plasmid repository, Addgene. The two reporter-gene solution is based on the principle that it is easier to distinguish signal from “noise” when the signal is reported by two or more detectors. Such coincidence detectors are a strategy employed in other fields. For instance, Positron Emission Tomography (PET) scans use this technology to detect cancerous tumors. In astrophysics, they are used to detect signals from space. And in the human body, our brain uses coincidence detection as part of its neural network. Building on this theory, Inglese and Cheng thought that if the reporter genes could be used together, researchers might be able to see instances when both reporters were active, providing more confidence that the test compound was having the sought after effect. To test this, they used firefly luciferase (FLuc) and Renilla luciferase (RLuc). As a result, the researchers were able to demonstrate the accuracy of the method by conducting a high-throughput screen to discriminate compounds with activity on a well-studied biological pathway versus those that were artifacts of direct reporter-gene interaction. “We now can use this method to see what signals are common between the two distinct reporters as an indication of what molecules should be pursued further,” said Inglese, head of the Assay Development and Screening Technology Laboratory in DPI. “The presence of two reporter-gene signals translates to a higher probability of a biological response rather than a compound interacting with a reporter.” According to Inglese, the improved method will save researchers a great deal of time and money in the long run. The next steps for his laboratory are to understand the increase in efficiency gained from using the new methodology, and whether multiple multiple reporter-gene combinations can further extend the fidelity and sensitivity of a response. “Our method represents a simple and accessible solution to a complex and pervasive problem,” Inglese said. “We are confident that scientists can use it to increase the predictability of drug screening results.” Posted November 2012 | ||||||||
| 600 | NCATS Science Featured at 26th NIH Research Festival | Researchers and staff from the National Center for Advancing Translational Sciences (NCATS) highlighted some of the Center’s recent science advances and new initiatives at the 26th Annual NIH Research Festival Oct. 9 – 12, 2012, on the NIH campus in Bethesda, Maryland. This year’s festival theme was “The NIH at 125: Today’s Discoveries, Tomorrow’s Cures,” and translation was a prominent topic for discussion. Topics such as “translation research in addiction, stress and anxiety,” and “how to put the ‘translational’ into your research” were two of many featured presentations. Steven Groft, Pharm. D., director of NCATS’ Office of Rare Diseases Research (ORDR) and P.J. Brooks, Ph.D., an ORDR program director with NCATS co-chaired a presentation about the NIH Clinical Center’s Bedside-to-Bench Program, which funds intramural and extramural collaborative research teams seeking to translate basic scientific findings into therapeutic interventions for patients and to increase understanding of important disease processes. Specifically, Groft and Brooks discussed the benefits of these collaborative research teams related to rare disease research. Marc Ferrer, Ph.D., in NCATS’ Division of Preclinical Innovation, spoke about drug screening using stem cell derived cellular disease models during the session “Disease in a dish — modeling human diseases using induced pluripotent stem cells.” More than 40 NCATS DPI researchers were listed as authors on posters about recent research at sessions during the festival. They included posters in the areas of cancer research, rare diseases, chemistry advances and core technologies. Click on each title below for details: A miniaturized screening assay to discover Pin1 inhibitors as probes of phosphorylation signaling Authors: M.I. Davis, D. Wei, M. Shen, D. Auld, M. Boxer, X.Z. Zhou, K.P. Lu, A. Simeonov High throughput screen to identify small molecule modulators in a cell-based model of AML Authors: R.E. Jones, C.Z. Chen, A.D. Schimmer, J. McKew, W. Zheng Discovery and development of small molecules that reduce PNC prevalence Authors: S. Patnaik, K. Frankowski, F. Schoenen, S. Huang, J. Norton, C. Wang, S. Titus, M. Ferrer, W. Zheng, N. Southall, V.W. Day, J. Aube, J.J. Marugan Discovery of novel Benzimidazole containing small molecules for the potential treatment of Chagas Disease Authors: D.K. Luci, W. Lea, M. Shen, A. Rodriguez, A. Jadhav, A. Simeonov, D.J. Maloney ADME assays in drug discovery and preclinical drug development research at TRND/NCATS/NIH Authors: KL.T. Nguyen, E.H. Kerns, X. Xin, J.C. McKew Discovery of a potent, small molecule inhibitor of R132H mutant isocitrate dehydrogenase 1 Authors: R. Pragani, M. Davis, N. Thorne, A. Simeonov, M. Shen, M.B. Boxer Discovery of novel general anesthetics using Apoferritin as a surrogate system Authors: G. Rai, W. Bu, W.A. Lea, D. Liang, B. Weiser, V. Setola, C.P. Austin, A. Simeonov, A. Jadhav, R. Eckenhoff, D.J. Maloney Structure-activity relationships of a novel inhibitor of BLM helicase Authors: A.S. Rosenthal, T.S. Dexheimer, G. Nguyen, O. Gileadi, I. Hickson, A. Simeonov, A. Jadhav, D.J. Maloney Identification and characterization of small-molecule chaperones of acid alpha glucosidase for potential treatment of Pompe disease Authors: M.K. Taylor, W. Westbroek, W.A. Lea, A.M. Gustafson, A. Velayati, W. Zheng, N. Southall, A. Simeonov, E. Goldin, E. Sidransky, J.J. Marugan, J. Xiao Genome-wide RNAi screening at the NIH through the Trans-NIH RNAi Screening Facility Authors: S.E. Martin, E. Buehler, Y. Chen, R. Guha, C. Klummp, P. Tuzmen, N.J. Caplen, C.P. Austin Posted November 2012 | ||||||||
| 599 | NCATS Collaborative Project Wins Award for Excellence in Technology Transfer | A collaborative research team, including nine experts from NCATS, was honored last month for its work on an investigational treatment for Niemann-Pick disease type C1, a rare genetic disease of cholesterol storage that eventually leads to neurodegeneration. Comprising investigators from four NIH institutes and one pharmaceutical company, the team won the Excellence in Technology Transfer Award for its work with 2-hydroxypropyl-β-cyclodextrin (HPβCD) as a potential treatment for a disease that has no Food and Drug Administration (FDA)-approved therapies. It is the first award of its kind to NCATS, recognizing laboratory employees and their partners who have outstanding accomplishments in transferring federally developed technology to the marketplace. The Federal Laboratory Consortium for Technology Transfer (FLC) of the mid-Atlantic region presented the award to the investigators at a ceremony on Aug. 30, 2012, in Cambridge, Maryland. Experts from NCATS, the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), the National Cancer Institute (NCI), the National Human Genome Research Institute (NHGRI) and Janssen Research & Development, LLC (Janssen) all participated in the research. Staff from NCATS’ Therapeutics for Rare and Neglected Diseases (TRND) program and from the Office of Policy, Communications and Strategic Alliances included: Christopher P. Austin, M.D., John McKew, Ph.D., Elizabeth Ottinger, Ph.D., Lili Portilla, M.P.A., Juan Marugan, Ph.D., Wei Zheng, Ph.D., Nuria Carillo-Carrasco, M.D., Xin Xu, Ph.D., and Pramod Terse, Ph.D. The research team selected HPβCD because studies in animal models have shown that it can reduce cholesterol and lipid storage in cells. By reducing this biochemical burden associated with Niemann-Pick type C1, the drug improves neurological pathology, decreases neurological dysfunction and increases lifespan. Aiming for a Rare Disease Treatment Sometimes, it can take a village to advance rare diseases research, particularly when aiming for a treatment. NIH understands that collaboration with industry, advocates and researchers is critical to moving the process forward. This research project ― one of 14 organized by TRND and selected for the 2012 regional FLC award ― is a model for this kind of innovative partnership. Each partner played a critical role in the project. Janssen provided the proprietary formulation of HPβCD and access to the FDA drug master file to NICHD and NCATS. NICHD’s Forbes Porter, M.D., Ph.D., is the project’s team leader and directed the research effort. NCATS’ McKew selected this TRND pilot project, and TRND project manager Ottinger coordinated efforts among the collaborators. Janssen’s Mark Kao, Ph.D., is participating in the preclinical research and biochemical analysis in support of the clinical study. NCI’s technology transfer specialist Alan Hubbs, Ph.D., and Portilla, acting director of the NCATS Office of Policy, Communications and Strategic Alliances, drafted and negotiated the associated agreements. TRND staff clinician Carillo-Carrasco developed the protocol and will facilitate coordination among the NIH Clinical Center and other NIH Institutes. Several academic institutions are performing the preclinical research, and a clinical trial agreement is in negotiation. Several recipients of the 2012 mid-Atlantic regional Federal Laboratory Consortium for Technology Transfer Award (left to right): Lili Portilla, M.P.A., acting director of the NCATS Office of Policy, Communications and Strategic Alliances; Elizabeth Ottinger, Ph.D., TRND project manager at NCATS; Alan Hubbs, Ph.D., technology transfer specialist at the National Cancer Institute; Forbes Porter, M.D., Ph.D., clinical director of the Eunice Kennedy Shriver National Institute of Child Health and Human Development and team lead for the project; and Steven Silber, M.D., vice president of established products, and Mark Kao, Ph.D., team lead in preclinical development drug safety sciences at Janssen Research & Development, LLC “Joint efforts by the NCATS and NICHD technology transfer team in developing and executing a collaborative agreement helped facilitate the quick accumulation of the preclinical results that we needed for the Investigational New Drug application to the FDA,” said NCATS Director Christopher P. Austin, M.D. “This agreement makes it possible for us to efficiently redistribute HPβCD to participating academic laboratories so that critical experiments can get under way.” Now, the team is one step closer to moving HPβCD forward as a potential treatment for Niemann-Pick type C1. Innovation to Accelerate Research Accelerating the research process is a primary focus of NCATS. The Center strives to create innovative methods and technologies to enhance the development, testing and implementation of diagnostics and therapeutics across a wide range of diseases. One of the ways the Center does this is by providing its research partners with the tools and expertise they need to advance their research faster and more efficiently. The NCATS Strategic Alliances office aims to make it easy for industry and academia to partner with NCATS laboratories and scientists, providing a complete array of services to support technology development and partnership activities. These services include negotiating standard forms and model agreements between NCATS and outside parties. These template agreements can help investigators with: The exchange of research materials under material transfer agreements. Collaborative research conducted under cooperative research and development agreements. Clinical studies to determine the safety and efficacy of new agents under clinical trial agreements. The exchange of confidential information under confidential disclosure agreements. Staff in the NCATS Strategic Alliances office also assist in reviewing employee invention reports, making recommendations to NIH’s Office of Technology Transfer regarding patent applications and licensing NCATS technologies. For questions about technology transfer and partnerships, email the NCATS Office of Strategic Alliances. Posted September 2012 | ||||||||
| 598 | Activating Key Cancer Enzyme Blocks Tumor Growth in Mice | Scientists have known for decades that cancer cells use more glucose than healthy cells, which can feed the growth of some tumors. Now, a team that includes researchers from NCATS has identified compounds that delay tumor formation in mice. The compounds target a specific form of pyruvate kinase, called PKM2, which governs how cancer cells use glucose. The study’s findings were published online in the Aug. 26, 2012, advance issue of Nature Chemical Biology. Biologists from the Koch Institute for Integrative Cancer Research at the Massachusetts Institute of Technology (MIT) in Cambridge led the research team, which included scientists from NCATS, the Structural Genomics Consortium at the University of Toronto and Harvard Medical School in Boston. “The last several years have brought an avalanche of new discoveries that have begun to explain a phenomenon of altered cancer cell metabolism first described almost 90 years ago,” said Christopher P. Austin, M.D., NCATS director and one of the paper’s authors. “This work provides a wonderful example of how molecular compounds can be used as tools to probe and understand biological processes and, at the same time, explore new drug targets in the fight against cancer.” How It Works The pyruvate kinase enzyme is involved in a critical energy-producing process known as glycolysis ― a process common in all cell types where glucose is broken down to produce adenosine triphosphate (ATP), the cell’s main energy source. Healthy cells and cancer cells use this process and enzyme differently. Studies have shown that the preferential expression of one form of pyruvate kinase, called PKM2, in cancer cells enables molecules produced through glycolysis to be used for new cell construction instead of energy. This altered metabolic state appears to be a fundamental aspect of many cancers, and reversing the process represents a new opportunity for cancer treatment. Lead study author Matthew Vander Heiden, M.D., Ph.D., a medical oncologist at MIT, along with colleagues at Harvard University, discovered that PKM2 is one of the main contributors to the altered cancer cell metabolism. The researchers found that replacing PKM2 with another form of pyruvate kinase, PKM1, actually stopped human lung cancer cells from forming tumors in mice. Vander Heiden and researchers from the NCATS Chemical Genomics Center, part of NIH’s Molecular Libraries Program, established a collaboration to test the theory that pharmacological activators of PKM2 would return cancer cells to a healthy metabolic state. Using high-throughput screening and medicinal chemistry, the team identified molecular compounds that could be used as drugs to activate PKM2. With these small molecules in hand, the team had the compounds they needed to examine whether restoring PKM2 activity would be detrimental to tumor growth ― similar to what they saw when they replaced PKM2 with PKM1 in earlier experiments. A Strategy for Cancer Therapy? To test whether activating PKM2 would slow or stop tumor growth, the investigators evaluated the PKM2 activators in mice. The team selected a drug called TEPP-46, which was well-tolerated in mice and provided maximum PKM2 activation. Mice with human tumor cells were divided randomly into two groups that received either the drug or placebo for seven weeks. At the end of the test, researchers found that TEPP-46 did not completely stop tumor development, but it did delay tumor growth and reduce the size of tumors. “It’s fair to say that perhaps activating pyruvate kinase could have some role in pushing tumors away from a program that allows them to efficiently grow,” Vander Heiden said. “Whether or not it would really be a viable drug in people is an open question.” Nonetheless, he admitted to being “cautiously optimistic.” The NIH Common Fund’s Molecular Libraries Program supported this research and the prior development of the PKM2 activators. Additional support was provided by NCATS. Posted September 2012 | ||||||||
| 597 | Collaboration May Help Uncover Treatments for Rare Neurologic Disease | NCATS researcher Sung-Wook Jang stands next to the high-throughput screening robotic system used to identify potential treatments for Charcot-Marie-Tooth disease. A research collaboration including scientists from NCATS and the University of Wisconsin–Madison, helped identify three promising molecular compounds from a collection of approved drugs to pursue as potential treatments for Charcot-Marie-Tooth disease (CMT), a genetic neurological disease for which there are no current treatments. The nonprofit CMT Association initiated and supported the university research, and findings were reported on July 20, 2012, in the ACS Chemical Biology journal. The research team screened nearly 3,000 approved and investigational drugs from the NCATS Pharmaceutical Collection, in a laboratory test, or assay, for CMT. Identifying an already approved drug that possibly is effective for another disease can have many advantages over developing a medicine from the start, including shortening the time it may take to apply for human clinical trials. "These findings demonstrate what can be accomplished when a disease foundation and the academic researchers it funds work with the therapeutic development experts at NCATS to translate basic research findings into the first steps of developing a drug," said Christopher P. Austin, former director of the NCATS Division of Preclinical Innovation. "At NCATS, we plan to form more successful collaborations like this one in the future." Each of us has a dozen genes or so that exist in more or fewer copies than normal in our genome. Called copy number variations, these genetic differences result from duplications and deletions of genes and can result in the production of too much or too little of a gene product such as a protein in a cell. A common form of CMT, called CMT disease type 1A (CMT1A), occurs from such a copy number variation, and other research has linked copy number variants to diseases, including breast cancer, Parkinson’s disease and Alzheimer’s disease. In CMT1A, a gene called peripheral myelin protein 22 (PMP22) occurs in multiple copies. As a result, excess PMP22 protein builds up in cells in the peripheral nervous system, disrupting proper nerve conduction and contributing to slow progressive degeneration of the muscles in the foot, lower leg, hand and forearm, and a mild loss of sensation in the limbs, fingers and toes. In search of compounds that inhibit the excess production of PMP22, the researchers collaborated to develop a novel assay, incorporating a regulatory element of the PMP22 gene that leads to its overexpression and subsequently contributes to CMT1A. In 2009, Sung-Wook Jang, the first author of the ACS Chemical Biology CMT study, joined the laboratory of NCATS investigator James Inglese, a chemical biologist with expertise in assay development and high-throughput screening, to work on the project. Jang, supported by the CMT Association, was a recent graduate student who trained with John Svaren, one of the paper’s authors, at the University of Wisconsin, Madison. Jang led the validation of the CMT1A assays. He also screened NCATS’ pharmaceutical collection in the assay and confirmed the findings in secondary tests. "Our decision to bring in Sung-Wook to champion this project enabled him to leverage his prior expertise in CMT and make rapid advances in the program," said Inglese. "Sung-Wook’s understanding of the underlying biology of CMT transitioned well to his training at NCATS in assay development, screening and data analysis. It is a model that we plan to use in the future and one that would benefit other disease organizations seeking to establish translational research programs." For the CMT1A assay, the researchers prepared two cell lines that each contained a unique reporter that would indicate to researchers those drugs that were targeting the PMP22 regulatory element. Only drugs registering in both cell lines were considered by researchers to have the desired effect. Jang used a technique called RNA silencing to demonstrate that the activity of the regulatory element from PMP22 could be reduced when factors critical to PMP22 expression were depleted from the cell. This increased the researchers’ confidence that the assay design was faithful to the biology of CMT, and enabled them to identify three medications — fenretinide, ovlanil and bortezomib — that substantially decreased PMP22 expression. The authors recommend that the assay strategy used successfully for CMT1A may be useful for other rare diseases caused by gene copy number variations, leading to improved monitoring of disease regulatory pathways in cells and identifying compounds to explore as potential treatments. They caution, though, that developing these findings into a treatment for CMT1A patients still could be an uphill climb and is prone to failures along the way ─ similar to any other therapeutic development effort. Further research still must demonstrate the effectiveness of such compounds in animal models and humans. For example, as a direct follow-up from the study, European collaborators funded by CMTA have begun to test proteasome inhibitors such as bortezomib, one of the drugs that decreased PMP22 expression, in a rat model of CMT in Europe. In addition, the CMT Association now is expanding the subtypes of CMT for researchers to study as part of the collaboration. The association also aims to create a human model system of CMT1A using induced pluripotent stem cells, a type of adult stem cell. And, researchers in Inglese’s laboratory at NCATS are utilizing new techniques to build next-generation assays for CMT1A that more accurately assess active compounds; they also are identifying other targets in the genome that may affect PMP22 expression. "The CMT Association’s Strategy to Accelerate Research (STAR) will continue to fund projects that contribute to our ultimate goal of a finding a first treatment for CMT," said Pat Livney, CMT Association chief executive officer. "I am confident the association, together with the dedicated world class scientific team led by Drs. Inglese and Svaren, is delivering the state-of-the-art results that will prove successful." Posted July 2012 | ||||||||
| 596 | An Epigenetic Strategy to Kill Cancer Tumors | A team of NIH-funded scientists has developed a new method that changes the way genes are regulated to effectively cause cancer tumors to shrink and die in the laboratory. Supported in part by a Penn State University Clinical and Translational Science Institute (CTSI) pilot grant award and research funding from the National Cancer Institute (NCI), Penn State professors Yanming Wang and Gong Chen recently published work in the Journal of Biological Chemistry suggesting that stopping the action of an enzyme called PAD4 (peptidylarginine deiminase 4) sets off a chain reaction of "molecular switches" in cancer cells. The effect is to switch the internal cell signals from growth to death. Funded in part by NIH’s Clinical and Translational Science Awards (CTSA) program, this multidisciplinary team, is hopeful that their discovery will aid in the development of anti-cancer drugs that only target cancerous tissue without damaging healthy cells and vital organs. Chemotherapy, a standard cancer treatment, damages both healthy and diseased cells. The studied anti-cancer drug has the potential to reduce or eliminate these side effects and improve chemotherapies for cancer patients. PAD4 alters proteins called histones that package and regulate DNA in a process called "epigenetics," which alters gene function without changing the DNA sequence. This process is often involved in activating and deactivating genes ― turning genes on and off. Interestingly, PAD4 has been found in concentrations greater than usual in numerous types of human cancers, such as breast and bone cancer. This PAD4 "overexpression" also appears to be involved in such autoimmune diseases as rheumatoid arthritis and multiple sclerosis. Wang and Chen are using cell cultures and mouse tumor models to explore the way excess PAD4 affects cells. With funds from NCI, the Wang group previously found that PAD4 blocks tumor suppressors, which stop tumor growth. This led them to suspect that they could block cancer growth by turning off PAD4. A PAD4 inhibitor was already known, but it could not easily get through the cell membrane, so Chen, a chemist, created several new compounds that could block PAD4 activity. Wang, who is a biochemist and molecular biologist, found that a low dose of one of these compounds, called YW3-56, killed tumor cells in culture and in a tumor mouse model, shrinking tumors by up to 50 percent. Cancer cells responded very quickly to the treatment, suggesting that the compound easily penetrated the cells. Wang and Chen found that YW3-56 can work in combination with a compound called SAHA (suberoylanilide hydroxamic acid), another gene inhibitor that acts epigenetically, to increase tumor death to up to 70 percent. This rate is similar to what the traditional chemotherapy drug doxorubicin achieves. Further, the dose needed to kill cancer cells does not harm normal, healthy cells, unlike traditional chemotherapy. "Because the PAD4 treatment appears to be less toxic, it could be an excellent alternative to current chemotherapy treatments," Wang said, "making it a promising agent for a variety of cancers and diseases that over-express PAD4." The researchers found that when the PAD4 inhibitor turns on tumor suppressor genes, the cell-programming systems that encourage cell growth turn off. In fact, blocking PAD4 encourages a process in which the cells recycle their own components. In the tumor cell lines and mouse tumor model tested, the cells began to completely dismantle themselves and die. As Chen and Wang continue to conduct experiments to generate enough information to perform human clinical trials, pharmaceutical companies are already expressing interest in their work. The researchers currently are focusing their efforts on using YW3-56 and other inhibitors in breast cancer, but these inhibitors have the potential to be used in a variety of cancer types and autoimmune disorders. "Without pilot funds from our CTSI, this collaborative research would not have gotten off the ground," Chen said. Posted July 2012 | ||||||||
| 595 | Understanding the Brain’s Response to Sugar Could Help Treat Obesity | Finding new biomarkers to better prevent, diagnose and treat diseases is one of many translational science challenges that NCATS is working to overcome. Biomarkers, such as cholesterol levels, are biological indicators of the presence, absence or stage of a disease. These can help scientists and clinicians better understand diseases, including obesity, and measure a patient’s response to an intervention or treatment. Although obesity is a growing public health problem, scientists still do not know much about how it develops. Seventy percent of American adults are overweight or obese, and the prevalence of obesity in children is three times higher than just a generation ago. Being overweight increases the risk of many other diseases, including heart disease, Type 2 diabetes, high blood pressure and cholesterol, and stroke. To develop better preventions and treatments, scientists first must understand obesity’s causes. Finding biomarkers for the condition could accelerate this process. Now, a team of researchers from Yale University, supported in part by a Clinical and Translational Sciences Award (CTSA) from NCATS, have used imaging technology to look at how the brain responds to sugar. This approach could improve scientists’ knowledge of the brain’s role in obesity and could lead to the development of new biomarkers for the condition. Published in the Jan. 2, 2013, issue of JAMA, the imaging study was a multidisciplinary effort involving experts from endocrinology, psychiatry, basic biology, imaging physics, nursing and biostatistics. Team-based approaches to complex translational science problems are at the heart of NCATS science, including in the CTSA program. Not All Sugar Is the Same In this case, investigators used brain imaging to reproduce in people what had been observed in mice: different brain responses depending on the type of sugar given. “Work from animal studies suggests a major component of the obesity problem resides in the brain,” explained Robert S. Sherwin, M.D., director of both the CTSA-supported Yale Center for Clinical Investigation (YCCI) and the Yale Diabetes Research Center (YDRC), which is funded in part by NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). “While basic research in animals can provide clues to these differences, this new imaging technique is one of the only ways right now for us to examine the human brain, which is far more complex.” Using functional MRI (fMRI) to measure blood flow to the brain, researchers can determine which brain areas are active in response to experimental interventions. The team tested 20 adult volunteers to see how their brains responded to both fructose and glucose. Fructose is widely used as a sweetener in foods, and high-fructose diets may contribute to obesity. Compared to glucose, fructose is sweeter and less effective at prompting the body to release the hormone insulin. Insulin acts in the brain to suppress hunger and lessen food’s pleasurable effect. In this way, fructose may increase appetite and eating. In fact, mice given fructose eat more, while glucose has the opposite effect. To see if humans respond similarly to mice, the researchers scanned the volunteers’ brains twice: once after they drank a glucose drink and once after a fructose drink, both of which contained the same number of calories. They discovered that glucose, but not fructose, reduced brain activity in areas that control appetite and the response to pleasurable aspects of food. The volunteers also reported feeling fuller and more satisfied after drinking glucose. These findings suggest that glucose triggers the brain to reduce the urge to eat. Brain responses to glucose and fructose ingestion show a distinctly different pattern. Glucose reduced blood flow and activity in brain regions that control appetite and reward (shown in blue at left). In contrast, appetite and reward regions remained active after fructose ingestion but activity in memory and sensory perception (shown in blue at right) was suppressed. These images represent composite data from 20 healthy adult volunteers. (Yale University Photo) Innovation Requires Specialized Support “The results were really exciting and quite striking,” said Kathleen A. Page, M.D., first author of the study, then a post-doctoral researcher at Yale who now is an assistant professor at the University of Southern California’s Keck School of Medicine. “We were able to translate those animal findings into studies in humans. It’s a perfect example of how translational science should work,” she added. But it couldn’t have come together without the diverse team of experts and CTSA-supported resources. “So many different elements of the study required special expertise,” Sherwin emphasized. “There is no way a single investigator could do that by himself. These projects require team research from multiple disciplines,” he added. CTSA-supported services enabled the imaging study at every point along the way. YCCI’s regulatory knowledge specialists helped Page and Sherwin write the study’s protocol so that it met the Institutional Review Board’s (IRB) standards for protection of human subjects. “Their expertise alone significantly reduced the time it took to get the study through the IRB review process,” said Sherwin. For example, support from the National Cancer Institute (NCI), NIDDK and NCATS’ CTSA program jointly fund Yale’s biostatistical support resource in the Yale Center for Analytical Sciences (YCAS), nursing staff in the Hospital Research Unit (HRU), and technicians in the Core Laboratory. A YCAS statistician performed the study’s data analysis. The YCCI helped recruit volunteers for the study. An HRU dietician prepared the drinks used in the study, while HRU nurses drew blood from the volunteers as they were being imaged. Core Laboratory technicians tested the blood to determine how levels of hormones such as insulin were affected by the sugary drinks. The CTSA also helped fund a critical equipment upgrade to the fMRI machine used in the study. In addition to support from the YCCI, the research team received support from both NCI and NIDDK. At Yale, the university maximizes its NIH and institutional support for clinical and translational research through joint support of core resources. Opening Doors for New Knowledge While the brain study’s findings are consistent with animal studies and other evidence, Sherwin cautions that the imaging technology is still an exploratory method at this stage. “Using fMRI to measure activity gives us a guide for where to look,” Sherwin explained. “Then, we can begin to focus in on these areas and determine what these changes in activity really mean.” The knowledge gained from this study will clear the path for researchers to delve into exactly how the sugars and feeding-related hormones interact with the brain regions identified in the study. Eventually, this information will clarify how various foods affect over-eating and weight gain, shedding light on the causes of obesity. “When we understand the mechanisms of how the brain responds to sugars, we can begin the process of identifying accurate drug targets and designing drugs and therapies to prevent and treat obesity,” Sherwin said. Sherwin’s team continues to explore the brain’s role in food and eating. They will soon publish findings of a similar study in which lean and obese adolescents’ brains were scanned while they consumed fructose and glucose. A related study in the same subjects looked at how the brain reacts when a participant views pictures of low and high calorie foods. In both studies, the brains of obese and lean children responded very differently. “So many chronic health problems begin with obesity. But you have to start somewhere,” Sherwin added. “The new imaging methods enable us to begin that process for the people already suffering from obesity. The knowledge gained also may help policymakers improve dietary recommendations and help public health departments develop better strategies to prevent obesity in healthy children and adults.” Posted December 2013 |
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