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News Article | May 8, 2017
Site: www.eurekalert.org

"Juicing" Th17 cells with FDA-approved small molecule β-catenin and p110δ inhibitors during in vitro expansion for adoptive T cell therapy (ACT) profoundly improves their therapeutic properties, report investigators at the Medical University of South Carolina (MUSC) in an article published online ahead of print on April 20, 2017 by JCI Insight. ACT involves harvesting T cells, rapidly amplifying and/or modifying them in the laboratory to boost their cancer-fighting ability, and then reinfusing them back to the patient to boost anticancer immunity. One challenge for ACT has been that the rapid expansion of T cells in the laboratory can cause them to age and wear out, decreasing their longevity after reinfusion. "Juicing" Th17 cells with the FDA-approved small molecules enhanced their potency, function and stem-like (less differentiated) quality, suggesting that they would persist better after reinfusion into patients, and also reduced regulatory T cells in the tumor microenvironment, which can blunt the immune response. These findings highlight novel investigative avenues for next-generation immunotherapies, including vaccines, checkpoint modulators, and ACT. "This is exciting because we might be able to overcome some of the delays and disadvantages of rapid expansion in the laboratory," explains senior author Chrystal M. Paulos, Ph.D., associate professor of immunology and Endowed Peng Chair of Dermatology at MUSC and a member of the MUSC Hollings Cancer Center. "We might be able to use fewer cells (for ACT) because we can pharmaceutically 'juice' these T cells to make them more fit in the oppressive tumor microenvironment." Building upon their previous findings that ICOS costimulation is critical for generating human TH17 cells and for enhancing their antitumor activity, an MUSC research team led by Paulos and including postdoctoral fellow Kinga Majchrzak report for the first time that repurposing FDA-approved small molecule drugs that inhibit two ICOS-induced pathways greatly enhances the antitumor potency of T cells. Several biologic properties of the Wnt/ β-catenin and P13Kδ pathways led the team to suspect that they supported the antitumor activities of Th17 cells. For example, these pathways are active in both regulating T cell cytokine production during the immune response and in promoting self-renewal of hematopoietic stem cells (HSCs) and sustaining HSCs in an undifferentiated state. So, they designed a series of experiments to determine whether these two pathways were also active in enhancing Th17 antitumor memory and effectiveness. To test this idea, they pharmaceutically inhibited PI3Kδ and β-catenin in Th17 cells (using idelalisib [CAL-101] to block the PI3Kδ pathway and indomethacin [Indo] to inhibit β-catenin)-anticipating that this would weaken Th17 cells' antitumor activity. To their surprise, the exact opposite occurred. ICOS-stimulated Th17 cells that were treated in vitro with CAL-101 plus Indo elicited a more potent antitumor response against melanoma in mice. "My post-doc student came to me and said, 'I think I made a mistake because the data are going in the opposite direction to what we originally predicted!" says Paulos. "So, she repeated the experiment several times but we kept getting the same result. The data showed that using drugs to inhibit these pathways actually made the Th17 cells even better at killing tumors." The team found that Th17 cells treated with CAL-101 express less FoxP3, suggesting that the drug suppresses Treg conversion while sustaining central memory-like Th17 cells. This finding is highly important because the phenotypic plasticity of Th17 cells in vivo allows their conversion to Tregs or Th1 cells with weak antitumor properties. These data suggest that treatment with CAL-101 can halt the development of these poorly therapeutic phenotypes and, thus, enhance the T cells' antitumor activity. While the findings were initially counterintuitive and perplexing from a mechanistic perspective, in retrospect Paulos sees that they make sense. "Essentially, the T cells are younger," explains Paulos. "We know that T cells used for ACT age and wear out over time. Somehow these drugs sustain their youth and function. They're able to keep all the properties of their youth-they expand better and they're more functional and handle the oppressive tumor microenvironment better." The discovery that existing FDA-approved drugs that block p110δ and β-catenin can make T cells more efficient tumor killers in vivo is an exciting prospect for Paulos' team. "From a clinical standpoint, this finding indicates that the therapeutic effectiveness of ACT could be improved by simple treatments with readily available drugs. It opens a lot of new investigative avenues for next-generation immunotherapy trials," she says. "This research offers tremendous promise for the treatment of patients with serious forms of skin cancer," says Dirk M. Elston, M.D., chair of the Department of Dermatology and Dermatologic Surgery at MUSC. Paulos has a patent on ICOS signaling in adoptive T cell transfer therapy (US 9133436), and Paulos, Majchrzak, and J.S. Bowers have a patent on pharmaceutical drug combinations or genetic strategies that instill durable antitumor T cell memory and activity (patent application P1685). Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org. The Hollings Cancer Center at the Medical University of South Carolina is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 120 faculty cancer scientists with an annual research funding portfolio of $44 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, visit http://www.


News Article | May 8, 2017
Site: www.eurekalert.org

No words can describe how happy Quanita Estell is to hear her six-year-old son come home with hilarious stories to tell. First, she enjoys his sense of humor, but mostly she's thrilled to see Joseph, who was diagnosed with autism spectrum disorder at 2, is becoming better able to communicate. It's been a long journey involving extensive treatment. But it's paid off. Now she gets to hear all about his adventures learning to surf in a program that helps children who have autism. Water and music seem to work wonders for him, but she knows they still have a tough road ahead. It's one reason she plans to enroll in a new nationwide genetic study to track down clues to the causes of autism with the goal of potentially developing new treatments. The study opens April 1 at the Medical University of South Carolina. "We try to get involved with anything that can help them," she says of a disorder that affects an estimated one out of 68 children. The prevalence of autism has increased significantly over the past two decades, and while some think that it may be leveling off, MUSC autism researcher Laura Carpenter, Ph.D., says the verdict's still out. What she does know is a lot has been spent researching a disorder where few treatments have been developed. Carpenter says she sees that potentially changing thanks to such studies as SC SPARK or Simons Foundation Powering Autism Research for Knowledge, which has launched a nationwide genetic study with the ambitious goal of enrolling 50,000 families to allow scientists to better understand the genetic changes that contribute to autism. MUSC is the South Carolina clinical partner for SPARK and will be serving the entire state. Anyone of any age on the autism spectrum, including Asperger's syndrome and PDD-NOS or pervasive developmental disorder/not otherwise specified, is eligible to join. Researchers also want parents and siblings to be a part of the study, which involves providing medical history and saliva samples. Individuals who enroll with parents' participation will receive compensation. There are more than 20 clinical sites nationwide participating. Participants who enroll get access to the SPARK resources online, which include webinars featuring national experts. "It's a real honor to be chosen," Carpenter says. "Many of the other clinical sites also selected are some of the leaders in autism research. This will open a lot of opportunities for MUSC to partner with other leaders in autism research." It's those partnerships that can lead to change. The majority of the money for research in autism has gone towards trying to figure out the genetic factors that lead to autism, and what researchers have found is that there are likely hundreds of genes that play a role, and to complicate matters, there are also likely environmental factors contributing to the development of the condition. "Now some experts are starting to talk about the 'autisms,' instead of autism -- meaning there are multiple pathways to developing autism. We think epigenetics plays a really big role, meaning that the environment probably influences which genes are active and which genes are ultimately implicated in autism. And we think it's probably a complex combination of genes and environment that lead to autism. What we know is that there are multiple genetic disorders that are associated with higher incidence of autism, but there is no one genetic change that results in autism. It's much more complicated than we had originally thought." What also has become clear is that researchers need a much larger sample size than anyone ever dreamed about. That's what SPARK is all about, she says. To put it in perspective, she considers a typical large, local study one that enrolls about 300 participants. The state's goal as part of the 50,000 being sought for recruitment is enrolling 1,000 participants, she says. "So, it's just a scale that has never been done before, and I think this is what is needed in order to move the field forward." The more representative the sample of participants, the better the research. That's why Carpenter wants to get the word out statewide. People can enroll at various community events, by coming to MUSC, and even asking for a home visit. Participants also can enroll online in the comfort and privacy of their own homes. "The state brings something really unique to the network in that we have a really diverse population. I think we have the potential to partner with people who don't necessarily participate in research very often. In order to get answers about a disorder that's so diverse, you really need to have everybody participate so that you have a representative sample," she says. "We will be holding their hand throughout the participation process. In order for the data to be most useful to the doctors and scientists, we really need people with autism, both their biological parents, and any siblings who are willing to participate." MUSC is committed to advancing treatments and care to improve the quality of life for those on the spectrum, she says. This initiative adds to many ongoing projects at MUSC, including: Carpenter is lead researcher on the CATS study and preliminary findings are showing that too many young adults on the autism spectrum are failing to thrive. "One of the things we know about autism is that if you intervene early, intensively with behavioral interventions, we can change the trajectory so that some kids will have really outstanding outcomes. So autism is treatable. But we also know that about 50 percent of kids will continue to have significant impairments, even if they get the best early intensive intervention - even the Cadillac of care, the best quality, the highest intensity - at least 50 percent of them will still need a lot of services after that. That tells us that we still need to develop other treatments." There's another advantage to SC SPARK that shows just how innovative a research project it is. It's a stepping stone to personalized medicine, she says. Should a treatment be developed for a certain genetic sample, for example, those participants who match the profile can be notified in case they want to take advantage of any treatment that has been shown to be potentially effective. The genetic analysis identifies people who carry known genes with autism links. According to SPARK, an estimated 5 to 10 percent of families are expected to receive genetic results in the first analysis. The genetic information gets re-analyzed every year, and as new autism genes are identified, additional genetic results will be returned. A genetic diagnosis is important because it can help in diagnosis and eliminate the need for additional testing, enable families to better understand the recurrence risk, identify opportunities to network with similar participants and be a pipeline to learn about clinical trials and/or treatments specific to their diagnoses. It also takes research to a new level and will enable autism studies of all types to get off the ground more quickly, something that's really needed, says Carpenter. MUSC is rolling this out in April, which is Autism Awareness month. April 2 marks an international celebration of Light it Up Blue, a day dedicated to raising awareness about the disorder. It's a good time to launch enrollment, she says. "This study is amazing and totally groundbreaking. Not only are we going to get this huge cohort of people and genetic information for this effort, but now these groups of SPARK participants are going to be notified when new ideas come on board. They'll be ready to go. One of the ideas is that autism may eventually be something that is treated with a more precision approach and, if that is the case and you have this really big sample of people, you might be able to pick out the ones you think will respond better for one treatment versus others."


Primary colorectal tumors secrete VEGF-A, inducing CXCL1 and CXCR2-positive myeloid-derived suppressor cell (MDSC) recruitment at distant sites and establishing niches for future metastases, report Medical University of South Carolina (MUSC) investigators in an article published online ahead of print on April 28, 2017 by Cancer Research. Liver-infiltrating MDSCs help bypass immune responses and facilitate tumor cell survival in the new location. This research illuminates mechanisms by which primary tumors contribute to premetastatic niche formation and suggests CXCR2 antagonists may reduce metastasis. Recent cancer research shows that premetastatic 'niches' form at sites far from the original tumor before new tumors occur. In colorectal cancer (CRC), these supportive microenvironments form in preferred secondary organs, such as the liver and lung, and facilitate the colonization, survival, and growth of metastasizing tumor cells. However, the mechanisms responsible for the formation of these premetastatic 'niches,' including what role(s) the primary tumor may play, are not well understood. It is critical to better understand the mechanics of CRC metastasis, as it is the second leading cause of cancer deaths in the US and patients with advanced cases often die because current treatments for widely metastasized disease are not effective. MUSC investigators led by Raymond N. DuBois, M.D., Ph.D., dean of the MUSC College of Medicine and professor of Biochemistry and Molecular Biology, have now illuminated how primary CRC tumors contribute to premetastatic 'niche' formation. "The idea that some sort of 'priming' needs to take place for metastasis to occur in distant organs - that there is some sort of activity in the future tumor location - is not new. But most research has focused on growth factors, chemokines and pro-inflammatory cytokines. There hasn't been much work looking at immune cell activity in distant organs prior to metastasis," explains DuBois. "We knew that the type and density of immune cells in the primary tumor plays a role in progression. For example, when more immature myeloid cells are present in the tumor, it becomes resistant to immune attack. But we didn't know what to expect in a metastatic model." To explore this area, the team first evaluated whether the presence of a primary tumor affected immune cell profiles in premetastatic liver and lung tissues of mice. They found that the presence of a primary cecal tumor caused MDSCs to begin infiltrating the liver before metastasis began. Working backward from this finding, they used a series of experiments to reveal the chain of events that led up to MDSC infiltration. Because CXCR2 is essential for drawing MDSCs out of the bloodstream and toward CRC tumors and colonic mucosa, the team began looking for CXCR2 and its ligands (CXCL1, CXCL2, and CXCL5) in mouse liver tissue. The team not only found that the ligand, CXCL1, attracted MDSCs from the bloodstream into premetastatic liver tissue, but also that administering a CXCR2 antagonist inhibited CXCL1 chemotaxis. This demonstrated that CXCR2 is required for CXCL1 to induce MDSC liver infiltration. In other words, the CXCL1-CXCR2 axis is required to recruit MDSCs to the liver. Importantly, they also found that liver- infiltrating MDSCs secrete factors that promote cancer cell survival and metastatic tumor formation without invoking the innate and adaptive immune responses. Next, because VEGF is known to induce CXCL1 expression in lung cancer, the research team examined whether VEGF secreted by CRC tumors also regulated CXCL1 expression. Their results demonstrated that VEGF-A secretion by primary CRC tumor cells stimulates macrophages to produce CXCL1. Interestingly, although VEGF-A knockdown inhibited liver metastasis, it did not affect the growth of the primary tumor. "We did not expect to find that a primary tumor could affect a distant organ before any of the cancer cells arrived on site," says DuBois. "We were surprised to see these changes before a single metastatic cell took up residence." Together, these studies reveal that VEGF-A secreted by the primary CRC tumor stimulates macrophages to produce CXCR1, which recruits CXCR2-expressing MDSCs from the bloodstream into healthy liver tissue. The MDSCs then create a premetastatic 'niche' or micro-environment where cancer cells can grow to form new tumors. These results demonstrate for the first time that cells in the primary tumor contribute to forming distant pre-metastatic 'niches' which facilitate the spread of disease. "Now that we know the primary tumor puts things in motion remotely prior to metastasis, we should be able to inhibit this process and have a positive impact on survival," explains DuBois. "We now know which molecules and immune cells are involved and that if we disrupt the CXCL1-CXCR2 axis we can possibly reduce the spread of disease. Both antibodies and small molecules can inhibit this pathway, but they have not yet been optimized. I hope these findings will speed up the development of inhibitors of the CXCR2 pathway." Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.


Co-administering a monoclonal antibody that neutralizes tumor-released soluble MHC I chain-related molecule (sMIC) improves anti-CTLA4 antibody therapy effectiveness and reduces treatment-related colitis, report Medical University of South Carolina (MUSC) investigators in an article published online May 17, 2017 by Science Advances. Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) can be thought of as an 'off switch' or 'immune checkpoint' for effector T cells that are activated to fight cancer tumors. Researchers have developed a therapy to block CTLA4, specifically, anti-CTLA4 antibody immunotherapy, to help sustain T-cell activation and improve patient survival. Unfortunately, while anti-CTLA4 therapy is highly effective in animals, response rates in humans vary widely and serious adverse events such as colitis (gastrointestinal inflammation) are common. For example, Ipilimumab, an FDA-approved anti-CTLA4 antibody therapy for advanced melanoma, is highly effective in controlling tumors in mice but has a response rate of only fifteen percent in humans. Clinical investigators have tried to improve the efficacy and safety of anti-CTLA4 therapy by combining it with other agents but response rates and toxicity remain suboptimal. A team of MUSC researchers led by Jennifer Wu, Ph.D., professor of Microbiology and Immunology, suspected that response disparities between humans and animals may be due to differences in immune modulators that human tumors express. "When we use animals to study therapies for humans we often neglect certain human-specific biological pathways simply because they don't exist in the animal," explains Wu. "MIC is one of those molecules that is expressed in human tumors but is absent in mice. We knew that the soluble form, sMIC, is highly immunosuppressive in humans and we knew it was important, but we had no way to study it. We had to create a new model." Their work to unravel these molecular-level differences has now paid off, with the discovery of a new combination therapy that dramatically improves CTLA4 therapy effectiveness and avoids therapy-induced colitis. The team developed a clinically relevant, MIC-transgenic spontaneous mouse tumor model that closely resembled the onco-immune dynamics seen in human cancers. Using this model, they investigated how tumor-derived, human sMIC affected anti-CTLA4 therapy. They found that high blood levels of sMIC not only reduced the antitumor efficacy of anti-CTLA4 therapy but also directly evoked colitis. "It was a total surprise, and we were a little nervous about the results," says Wu. "So, we repeated the test using multiple models and antibodies and different batches of animals to make sure it was reproducible and that what we were seeing was real. Sometimes knowledge itself gets in the way. Because there are certain accepted beliefs that make you think what you're seeing can't be true-that it's impossible. But when multiple experiments are all coming up with the same results, what can you say? That's when we have to let go and come to a new understanding." Next, the team co-administered an antibody called B10G5 that neutralizes sMIC, alongside anti-CTLA4 therapy. The new combination therapy not only remarkably improved anti-CTLA4 immunotherapy effectiveness, but also alleviated therapy-induced colitis. "We've been studying B10G5 for a while and published a paper in Clinical Cancer Research in 2015 demonstrating that using B10G5 to target sMIC can alleviate tumor-induced immune suppression and also has a huge immune-stimulating ability," explains Wu. "So those results led us to think it would be a good strategy to combine B10G5 with antibodies that target immune checkpoint molecules, the 'off-switch' of an ongoing immune response." Finally, inspired by a case study published in 2006, the team decided to try to validate its current findings in humans. The original case reported a melanoma patient who developed anti-MIC autoantibody during anti-CTLA4 therapy and had a superior therapeutic response. So, they contacted a long-time collaborator at Oregon Health and Science University and Knights Cancer Center to obtain plasma samples collected during a clinical trial they were conducting in metastatic prostate cancer patients. Wu's team looked for anti-sMIC autoantibodies in samples from ten patients receiving anti-CTLA4 therapy with Ipilimumab. One sample showed high levels of anti-MIC autoantibody. When the team followed up with their colleague, it turned out that this particular cancer patient not only demonstrated a remarkable therapeutic response (his prostate-specific antigen fell from 191 to 4.6 ng/ml after eight treatment cycles) but also did not develop autoimmune colitis. That case reinforced the team's preclinical in vivo findings that coadministering the sMIC-neutralizing antibody (B10G5; CanCure, LLC) enhances anti-CTLA4 therapy and deters colitis. Overall, these results indicate a new, powerful combination immunotherapy for cancer. They also suggest that pre-screening serum sMIC levels might help clinicians to identify patients who are most likely to have a positive therapeutic response. "I hope that our findings will inspire investigators to revisit other cancer immunotherapies that were successful in animals but presented no efficacy in humans," says Wu. "Anti-CTLA4 therapy is approved for melanoma and also is still in trials for other cancers. Maybe our study will inspire clinical investigators to think about screening their patients to identify who will be a better responder versus a poor responder to anti-CTLA4 therapy." Wu is on the scientific advisory board of CanCure, LLC. Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.


News Article | May 19, 2017
Site: www.eurekalert.org

Chronic pancreatitis (long-standing inflammation of the pancreas) (CP) is a challenging disease for health care practitioners because it is difficult to diagnose and treat. Although its annual incidence rate in the United States is low (5 to 12 per 100,000 persons), hospital admissions due to CP are on the rise. CP is characterized by severe abdominal pain and irreversible damage to the pancreas. In the past decade new medical and surgical treatments have emerged that enable multidisciplinary teams to better recognize and manage this disease. In 2014, gastrointestinal specialists at the Medical University of South Carolina (MUSC), led by David B. Adams, M.D., professor of surgery and an expert in CP, organized the first international exchange of information on these advancements. The "2014 International Symposium on the Medical and Surgical Treatment of Chronic Pancreatitis" brought together experts from the fields of medicine, surgery, psychology, physiology, pharmacology and genetics. Last month, a textbook covering the information that came out of that meeting was published (Wiley-Blackwell, April 2017). "Pancreatitis: Medical and Surgical Management" (ISBN: 978-1-118-91712-1) covers acute pancreatitis (sudden inflammation that lasts a short time) as well as CP. Adams is the chief editor. Co-editors are Peter B. Cotton, M.D., professor of medicine at MUSC; Nicholas J. Zyromski, M.D., associate professor of surgery at Indiana University School of Medicine; and John A. Windsor, MBChB, M.D., professor of surgery at Mercy Hospital in New Zealand. The book provides gastroenterologists and gastrointestinal surgeons with an evidence-based approach to the most recent developments in the diagnosis and clinical management of pancreatitis. In addition to new surgical procedures such as endoscopic biliary intervention and minimally invasive necrosectomy, these advances include medical therapies, such as antiprotease, lexipafant, probiotics and enzyme treatment. "This book is the latest information from international experts in all of the relevant disciplines of medicine," says Adams. "This represents the first time all of these experts have come together to share their knowledge and experience." MUSC will host a second international CP symposium in 2018 in Charleston, South Carolina. International experts from the fields of medicine, surgery, psychology, physiology, pharmacology and genetics will confer and exchange ideas to identify the direction, trends and developments in the diagnosis and management of CP that are needed to enhance clinical effectiveness, encourage adoption by healthcare providers, and engage patients in best practice and cost-effective care. Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.


A new genetic approach in worms provides a roadmap for the mesenchymal-to-epithelial communication that drives human cancer, report researchers at the Medical University of South Carolina Hollings Cancer Center in Developmental Cell Some major cell-to-cell communication networks were first studied in worms. Now those worms, Caenorhabditis elegans, are being used to understand the influence of cancer mutations on those networks, report researchers at the Medical University of South Carolina (MUSC) in the May 22, 2017 issue of Developmental Cell. Because many genes involved in cell communication are often conserved across species, C. elegans is an ideal organism to study the genes that influence them. This makes the worm a very useful genetic tool for exploring the basis of human cancer, according to Gustavo Leone, Ph.D., director of MUSC Hollings Cancer Center and the Grace E. DeWolff Endowed Chair in Medical Oncology. "If the genetic network within tumor cells or epithelial cells is similar among C. elegans, mice and humans, the communication of neighboring cells with epithelial cells in tumors at some level might also be similar," explains Leone. Leone is corresponding author on the study along with his colleague Helen Chamberlin, Ph.D., a C. elegans expert in The Ohio State University Department of Molecular Genetics. The two laboratories collaborated to approach a big-picture question about cancer. A number of important individual cancer genes have been discovered by Leone and many others, but is there a way to identify all of the genes-a genetic signature-involved in cell-to-cell communication in cancer? In particular, Leone sought to identify which genes within the neighboring cells that make up the tumor microenvironment could control tumor and epithelial cell proliferation. Yet determining networks of cell-to-cell communication requires a genome-wide screen that tests genes individually, an approach that is impractical in mice. This was where C. elegans became so essential to answering the group's question. Part of the tumor microenvironment is supported by mesodermal cells, which send molecular signals to epithelial cells that tightly control their proliferation. This mesodermal-epithelial communication is needed in normal conditions, such as during pregnancy and wound healing, but is disrupted in cancer. Similar communication exists between those cells in the egg-laying organ of C. elegans called the vulva. When similarly disrupted during worm development, this network can unleash epithelial cell proliferation that causes a multivulva, or Muv, feature. This feature, which becomes prominent when adult worms reach one millimeter in length, is easily visible under a microscope. First author Huayang Liu, Ph.D., was a student in Leone's laboratory who helped design and build the genome-wide screen to identify which mesoderm genes worms need to prevent such Muv defects. Very importantly, the worms were also given a human cancer mutation in the gap-1 gene to sensitize their epithelial cells to communication signals that encourage proliferation. In this way, the screen was designed to test the influence of each of the nearly 20,000 C. elegans genes on the proliferation of epithelial cells carrying a common cancer-sensitizing mutation. From the entire C. elegans genome, the screen uncovered 39 worm mesoderm genes that, when reduced in expression, encouraged microscopic Muv defects suggestive of epithelial cell proliferation. Thirty-three of those genes are conserved in humans. The identities of those genes were unexpected, according to the authors. They are not involved in 33 random processes that control cell behavior. Rather, many of them converge on hubs of regulation that control major gene expression signatures. It appeared that the mesodermal-epithelial communication network containing this 33-gene signature could be fundamental to cell behavior in worms. Yet was it relevant in higher animals? The group tested three of these 39 genes in female mice and found that reducing their expression within fibroblasts (another mesodermal-type cell) encouraged proliferation in mammary epithelial cells. There was a final need to prove the relevance of this work to human cancer. Tests were performed in the stroma-part of the microenvironment-of tumor samples taken from human breast cancer patients. As suspected, the expression of those 33 genes was very different between normal and tumor stroma. In further experiments, depletion of 22 of these genes in human fibroblasts encouraged proliferation of breast tumor epithelial cells. The group had confirmed a genetic signature of mesodermal-epithelial communication unique to cell proliferation in cancer. This study uncovered a small sector of the network that allows mesodermal and epithelial cells to communicate. Yet the screen is designed to work with many cancer-sensitizing genes other than gap-1, which can reveal more of the network. Leone's group has repeated the screen using another genetic mutation that seems to influence completely different cellular processes involved in cell-to-cell communication. A complete roadmap will guide new cancer therapies, according to Leone. "This provides an avenue to understand why drugs work or don't work, and it provides new targets that we can now begin to drug," says Leone. Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents, and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion. MUSC operates a 750-bed medical center, which includes a nationally recognized Children's Hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute designated center) Level I Trauma Center, and Institute of Psychiatry. For more information on academic information or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org. The Hollings Cancer Center at the Medical University of South Carolina is a National Cancer Institute-designated cancer center and the largest academic-based cancer research program in South Carolina. The cancer center comprises more than 120 faculty cancer scientists with an annual research funding portfolio of $44 million and a dedication to reducing the cancer burden in South Carolina. Hollings offers state-of-the-art diagnostic capabilities, therapies and surgical techniques within multidisciplinary clinics that include surgeons, medical oncologists, radiation therapists, radiologists, pathologists, psychologists and other specialists equipped for the full range of cancer care, including more than 200 clinical trials. For more information, visit http://www.


News Article | May 5, 2017
Site: www.scientificcomputing.com

A collaboration between stroke neurologists at the Medical University of South Carolina (MUSC) and bioengineers at the University of Massachusetts has led to the creation of a realistic, 3D-printed phantom of a stenotic intracranial artery that is being used to standardize protocols for high-resolution MRI, also known as vessel-wall MRI, at a network of U.S. and Chinese institutions, according to an article published online March 9, 2017 by the Journal of NeuroInterventional Surgery. High-resolution or vessel-wall MRI has been used to study the plaque components in vessels in the brain for more than ten years and has the potential to elucidate the underlying pathology of intracranial atherosclerotic disease (ICAD), the leading cause of stroke worldwide, as well as to gauge patient risk and inform clinical trials of new therapies. However, progress has been stymied by the lack of standardization in high-resolution MRI protocols, which poses an obstacle to multicenter trials. "There is a lot of exciting research that is possible with high-resolution MRI techniques, but it has much less opportunity to affect patient care if it can't be systematically distributed to multiple sites and multiple populations," says Tanya N. Turan, M.D., director of the MUSC Stroke Division and senior author of the article. To overcome this obstacle, Turan worked with bioengineers at the University of Massachusetts to produce a phantom of a stenotic intracranial vessel using imaging sequences obtained from a single patient with ICAD at MUSC. The 3-D printed ICAD phantom mimics both the stenotic vessel and its plaque components, including the fibrous cap and the lipid core. The phantom is being shared with collaborating institutions so that it can be used to standardize high-resolution MRI protocols. The imaging data presented in the Journal of NeuroInterventional Surgery article demonstrate the feasibility of using the phantom for standardization and were obtained from six U.S. and two Chinese sites. Producing the phantom was a major step in the right direction for standardizing high-resolution MRI ICAD protocols. However, several more years may be necessary to complete the process. The next major challenge for these investigators will be establishing parameters for MRI machines from a variety of manufacturers. So far, MRI parameters have been established for Siemens and GE systems but work is still under way on Philips systems. The phantom is also being shared with sites in China, where the burden of intracranial stenosis is especially high. Turan is collaborating with Weihai Xu, M.D., of Peking Union Medical College, the lead Chinese site, to collect additional data to assess interrater reliability among the participating institutions. Once high-resolution MRI protocols have been standardized and good interrater reliability demonstrated, the international team plans to conduct a prospective observational trial to examine risk prediction at participating centers, which would more quickly meet the required patient enrollment than would a trial conducted in the U.S. alone. "We're only going to be able to advance the field more quickly if we work together," says Turan. "The phantom gives us the tool to be able to work together."


News Article | May 5, 2017
Site: www.scientificcomputing.com

A collaboration between stroke neurologists at the Medical University of South Carolina (MUSC) and bioengineers at the University of Massachusetts has led to the creation of a realistic, 3D-printed phantom of a stenotic intracranial artery that is being used to standardize protocols for high-resolution MRI, also known as vessel-wall MRI, at a network of U.S. and Chinese institutions, according to an article published online March 9, 2017 by the Journal of NeuroInterventional Surgery. High-resolution or vessel-wall MRI has been used to study the plaque components in vessels in the brain for more than ten years and has the potential to elucidate the underlying pathology of intracranial atherosclerotic disease (ICAD), the leading cause of stroke worldwide, as well as to gauge patient risk and inform clinical trials of new therapies. However, progress has been stymied by the lack of standardization in high-resolution MRI protocols, which poses an obstacle to multicenter trials. "There is a lot of exciting research that is possible with high-resolution MRI techniques, but it has much less opportunity to affect patient care if it can't be systematically distributed to multiple sites and multiple populations," says Tanya N. Turan, M.D., director of the MUSC Stroke Division and senior author of the article. To overcome this obstacle, Turan worked with bioengineers at the University of Massachusetts to produce a phantom of a stenotic intracranial vessel using imaging sequences obtained from a single patient with ICAD at MUSC. The 3-D printed ICAD phantom mimics both the stenotic vessel and its plaque components, including the fibrous cap and the lipid core. The phantom is being shared with collaborating institutions so that it can be used to standardize high-resolution MRI protocols. The imaging data presented in the Journal of NeuroInterventional Surgery article demonstrate the feasibility of using the phantom for standardization and were obtained from six U.S. and two Chinese sites. Producing the phantom was a major step in the right direction for standardizing high-resolution MRI ICAD protocols. However, several more years may be necessary to complete the process. The next major challenge for these investigators will be establishing parameters for MRI machines from a variety of manufacturers. So far, MRI parameters have been established for Siemens and GE systems but work is still under way on Philips systems. The phantom is also being shared with sites in China, where the burden of intracranial stenosis is especially high. Turan is collaborating with Weihai Xu, M.D., of Peking Union Medical College, the lead Chinese site, to collect additional data to assess interrater reliability among the participating institutions. Once high-resolution MRI protocols have been standardized and good interrater reliability demonstrated, the international team plans to conduct a prospective observational trial to examine risk prediction at participating centers, which would more quickly meet the required patient enrollment than would a trial conducted in the U.S. alone. "We're only going to be able to advance the field more quickly if we work together," says Turan. "The phantom gives us the tool to be able to work together."


News Article | May 5, 2017
Site: www.eurekalert.org

Platelets promote immune tolerance to certain cancers by suppressing T cells and adoptive T cell therapy may be enhanced by adding antiplatelet drugs, report researchers at the Medical University of South Carolina in Science Immunology Blood platelets help disguise cancer from the immune system by suppressing T cells, report scientists at the Medical University of South Carolina (MUSC) in the May 5, 2017 issue of Science Immunology. In extensive preclinical tests, a promising T cell therapy more successfully boosted immunity against melanoma when common antiplatelet drugs such as aspirin were added. Zihai Li, M.D., Ph.D., senior author on the article, is chair of the MUSC Department of Microbiology and Immunology, the program leader for the Cancer Immunology Research Program at MUSC Hollings Cancer Center, and the SmartState® Sally Abney Rose Chair in Stem Cell Biology & Therapy. Li studies how tumors hide themselves from the immune system. Li's team found that platelets release a molecule that suppresses the activity of cancer-fighting T cells. That molecule, unsurprisingly, was TGF-beta, which has been recognized for decades for its role in cancer growth. Yet this study is the first of its kind. Most TGF-beta is inactive. Li and his group found that the surface of platelets has a protein called GARP, a molecular hook that is uniquely able to trap and activate TGF-beta. Platelets, which are small cell fragments that circulate throughout the blood and are normally involved in clotting, become the major source of activated TGF-beta that invading tumor cells use to suppress T cells. In other words, platelets help give tumors their invisibility cloak from the immune system. Scientists have known for several years that certain cancers suppress T cells to avoid the immune system. That is why adoptive T cell therapy is one of the most promising advances in modern cancer treatment. It is a type of immunotherapy that awakens the immune system by retraining a patient's T cells to recognize their cancer. T cells are isolated from a patient's blood and retrained, or "primed," to recognize tumor cells. They are then injected back into the patient's bloodstream where they can now hunt and fight cancer. There was some evidence that platelets might make cancer worse. For example, patients who have excessive clotting related to their cancer almost always have a worse prognosis, according to Li. "Over the years, it has become appreciated that platelets are doing more than just clotting," says Li. The first clue that cancer-fighting T cells might be suppressed by the body's own clotting system came when the researchers gave melanoma to mice with genetically defective platelets. Melanoma tumors grew much more slowly and primed T cells were much more active than in mice with normal platelets. Next, the team isolated platelets and T cells from blood drawn from humans and mice. In both cases, platelets with activated clotting activity suppressed T cell response. It then used mass spectrometry to thoroughly identify the molecules released by activated platelets that most suppressed T cell activity. The molecule with the most T cell suppression was TGF-beta. Li and his team then studied how platelets activate TGF-beta. In genetically modified mice without GARP, the molecular hook on the surface of platelets, adoptive T cell therapy was more successful at controlling melanoma. This meant that platelets without the ability to grab and activate TGF-beta were not able to suppress cancer-fighting T cells. Similar experiments confirmed this result in mice with colon carcinoma. Finally, mice with normal platelets that were given melanoma and then adoptive T cell therapy survived longer and relapsed less when aspirin and clopidogrel, two antiplatelet drugs, were added. The researchers noted that antiplatelet drugs by themselves were not successful in combating melanoma in their experiments. This study could inform future treatment of melanoma and other cancers and offers a sound reason to test antiplatelet drugs in clinical trials of adoptive T cell therapy. In patients with melanoma or other cancers, adoptive T cell therapy may be successful if highly available platelet-blocking drugs such as aspirin are added to the treatment. However, the current standard of care for melanoma is not adoptive T cell therapy, but so-called checkpoint inhibitors. Li and his group want to know if combination therapy with antiplatelet drugs could improve existing cancer treatment. They are waiting for approval to begin a clinical trial that will test certain checkpoint inhibitors in combination with aspirin and clopidogrel for the treatment of patients with advanced cancers. Li's trial will complement clinical trials that are already testing adoptive T cell therapy as a single treatment for cancer. "I'm very excited about this," says Li. "We can test simple, over-the-counter antiplatelet agents to really improve immunity and make a difference in how to treat people with cancer." Founded in 1824 in Charleston, The Medical University of South Carolina is the oldest medical school in the South. Today, MUSC continues the tradition of excellence in education, research, and patient care. MUSC educates and trains more than 3,000 students and residents in six colleges (Dental Medicine, Graduate Studies, Health Professions, Medicine, Nursing, and Pharmacy), and has nearly 13,000 employees, including approximately 1,500 faculty members. As the largest non-federal employer in Charleston, the university and its affiliates have collective annual budgets in excess of $2.2 billion, with an annual economic impact of more than $3.8 billion and annual research funding in excess of $250 million. MUSC operates a 700-bed medical center, which includes a nationally recognized children's hospital, the Ashley River Tower (cardiovascular, digestive disease, and surgical oncology), Hollings Cancer Center (a National Cancer Institute-designated center), Level I Trauma Center, Institute of Psychiatry, and the state's only transplant center. In 2016, U.S. News & World Report named MUSC Health the number one hospital in South Carolina. For more information on academic programs or clinical services, visit musc.edu. For more information on hospital patient services, visit muschealth.org.


TEL-AVIV, Israel, April 20, 2017 (GLOBE NEWSWIRE) -- RedHill Biopharma Ltd. (NASDAQ:RDHL) (Tel-Aviv Stock Exchange:RDHL) (“RedHill” or the “Company”), a specialty biopharmaceutical company primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for gastrointestinal and inflammatory diseases and cancer, today announced the publication of an article describing the positive results from the Phase I clinical study with YELIVA® (ABC294640)1 in advanced solid tumors. The article2, entitled “A Phase I Study of ABC294640, a First-in-Class Sphingosine Kinase-2 Inhibitor, in Patients with Advanced Solid Tumors”, was authored by scientists from the Medical University of South Carolina (MUSC) Hollings Cancer Center and Apogee Biotechnology and was published in Clinical Cancer Research. The article is available online on the journal’s website3. YELIVA® is a Phase II-stage, proprietary, first-in-class, orally-administered sphingosine kinase-2 (SK2) selective inhibitor with anticancer and anti-inflammatory activities, targeting multiple oncology, inflammatory and gastrointestinal indications. By inhibiting the SK2 enzyme, YELIVA® blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid signaling molecule that promotes cancer growth and pathological inflammation. The open-label, dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) first-in-human Phase I study with YELIVA® treated 21 patients with advanced solid tumors, most of whom were gastrointestinal cancer patients, including pancreatic, colorectal and cholangiocarcinoma cancers. The Phase I study was conducted at the MUSC Hollings Cancer Center and led by Principal Investigators Melanie Thomas, MD, and Carolyn Britten, MD. The primary objectives of the study were to identify the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) and to evaluate the safety of YELIVA®. The secondary objectives of the study were to determine the pharmacokinetic (PK) and pharmacodynamic (PD) properties of YELIVA® and to assess its antitumor activity. Final results from the Phase I study with YELIVA® in patients with advanced solid tumors confirmed that the study successfully met its primary and secondary endpoints, demonstrating that the drug is well-tolerated and can be safely administered to cancer patients. There was one partial response in a patient with cholangiocarcinoma and six patients had stable disease as their best response. The study included the first-ever longitudinal analyses of plasma S1P levels as a potential PD biomarker for activity of a sphingolipid-targeted drug. The administration of YELIVA® resulted in a rapid and pronounced decrease in S1P levels over the first 12 hours, with return to baseline at 24 hours, which is consistent with clearance of the drug. A Phase II study with YELIVA® for the treatment of advanced hepatocellular carcinoma (HCC) is ongoing at MUSC Hollings Cancer Center. The study is supported by a grant from the NCI, awarded to MUSC, which is intended to fund a broad range of studies on the feasibility of targeting sphingolipid metabolism for the treatment of a variety of solid tumor cancers, with additional support from RedHill. A Phase Ib/II study with YELIVA® for the treatment of refractory or relapsed multiple myeloma is ongoing at Duke University Medical Center. The study is supported by a $2 million grant from the NCI Small Business Innovation Research Program (SBIR) awarded to Apogee, in conjunction with Duke University, with additional support from RedHill. A Phase I/II clinical study evaluating YELIVA® in patients with refractory/relapsed diffuse large B-cell lymphoma and Kaposi sarcoma patients is ongoing at the Louisiana State University Health Sciences Center. The study is supported by a grant from the NCI awarded to Apogee, with additional support from RedHill. A Phase Ib study to evaluate YELIVA® as a radioprotectant for prevention of mucositis in head and neck cancer patients undergoing therapeutic radiotherapy is planned to be initiated in the third quarter of 2017. YELIVA® recently received FDA Orphan Drug designation for the treatment of cholangiocarcinoma. RedHill plans to initiate a Phase IIa clinical study with YELIVA® in patients with advanced, unresectable, intrahepatic and extrahepatic cholangiocarcinoma in the third quarter of 2017. A Phase II study to evaluate the efficacy of YELIVA® in patients with moderate to severe ulcerative colitis is planned to be initiated in the second half of 2017. About YELIVA® (ABC294640): YELIVA® (ABC294640) is a Phase II-stage, proprietary, first-in-class, orally-administered, sphingosine kinase-2 (SK2) selective inhibitor with anticancer and anti-inflammatory activities. RedHill is pursuing with YELIVA® multiple clinical programs in oncology, inflammatory and gastrointestinal indications. By inhibiting SK2, YELIVA® blocks the synthesis of sphingosine 1-phosphate (S1P), a lipid-signaling molecule that promotes cancer growth and pathological inflammation. SK2 is an innovative molecular target for anticancer therapy because of its critical role in catalyzing the formation of S1P, which is known to regulate cell proliferation and activation of inflammatory pathways. YELIVA® was originally developed by U.S.-based Apogee Biotechnology Corp. and completed multiple successful pre-clinical studies in oncology, inflammation, GI and radioprotection models, as well as the ABC-101 Phase I clinical study in cancer patients with advanced solid tumors. The Phase I study included the first-ever longitudinal analysis of plasma S1P levels as a potential pharmacodynamic (PD) biomarker for activity of a sphingolipid-targeted drug. The administration of YELIVA® resulted in a rapid and pronounced decrease in S1P levels, with several patients having prolonged stabilization of disease. YELIVA® received Orphan Drug designation from the U.S. FDA for the treatment of cholangiocarcinoma. The development of YELIVA® was funded to date primarily by grants and contracts from U.S. federal and state government agencies awarded to Apogee Biotechnology Corp., including the U.S. National Cancer Institute, the U.S. Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA), the U.S. Department of Defense and the FDA Office of Orphan Products Development. About RedHill Biopharma Ltd.: RedHill Biopharma Ltd. (NASDAQ:RDHL) (Tel-Aviv Stock Exchange:RDHL) is a specialty biopharmaceutical company headquartered in Israel, primarily focused on the development and commercialization of late clinical-stage, proprietary, orally-administered, small molecule drugs for the treatment of gastrointestinal and inflammatory diseases and cancer. RedHill has a U.S. co-promotion agreement with Concordia for Donnatal®, a prescription oral adjunctive drug used in the treatment of IBS and acute enterocolitis, as well as an exclusive license agreement with Entera Health for EnteraGam®, a medical food intended for the dietary management, under medical supervision, of chronic diarrhea and loose stools. RedHill’s clinical-stage pipeline includes: (i) RHB-105 - an oral combination therapy for the treatment of Helicobacter pylori infection with successful results from a first Phase III study; (ii) RHB-104 - an oral combination therapy for the treatment of Crohn's disease with an ongoing first Phase III study, a completed proof-of-concept Phase IIa study for multiple sclerosis and QIDP status for nontuberculous mycobacteria (NTM) infections; (iii) BEKINDA® (RHB-102) - a once-daily oral pill formulation of ondansetron with an ongoing Phase III study for acute gastroenteritis and gastritis and an ongoing Phase II study for IBS-D; (iv) RHB-106 - an encapsulated bowel preparation licensed to Salix Pharmaceuticals, Ltd.; (v) YELIVA® (ABC294640) - a Phase II-stage, orally-administered, first-in-class SK2 selective inhibitor targeting multiple oncology, inflammatory and gastrointestinal indications; (vi) MESUPRON - a Phase II-stage first-in-class, orally-administered protease inhibitor, targeting pancreatic cancer and other solid tumors and (vii) RIZAPORT® (RHB-103) - an oral thin film formulation of rizatriptan for acute migraines, with a U.S. NDA currently under discussion with the FDA and marketing authorization received in two EU member states under the European Decentralized Procedure (DCP). More information about the Company is available at: www.redhillbio.com. 1 YELIVA® is an investigational new drug, not available for commercial distribution. 2 The article was authored by Carolyn D. Britten, Melanie B. Thomas, Elizabeth Garrett-Mayer, Steven H. Chin, Keisuke Shirai, Besim Ogretmen, Tricia A. Bentz, Alan Brisendine, Kate Anderton, Susan L. Cusack, Lynn W. Maines, Yan Zhuang and Charles D. Smith. This press release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995. Such statements may be preceded by the words “intends,” “may,” “will,” “plans,” “expects,” “anticipates,” “projects,” “predicts,” “estimates,” “aims,” “believes,” “hopes,” “potential” or similar words. Forward-looking statements are based on certain assumptions and are subject to various known and unknown risks and uncertainties, many of which are beyond the Company’s control, and cannot be predicted or quantified and consequently, actual results may differ materially from those expressed or implied by such forward-looking statements. Such risks and uncertainties include, without limitation, risks and uncertainties associated with (i) the initiation, timing, progress and results of the Company’s research, manufacturing, preclinical studies, clinical trials, and other therapeutic candidate development efforts; (ii) the Company’s ability to advance its therapeutic candidates into clinical trials or to successfully complete its preclinical studies or clinical trials; (iii) the extent and number of additional studies that the Company may be required to conduct and the Company’s receipt of regulatory approvals for its therapeutic candidates, and the timing of other regulatory filings, approvals and feedback; (iv) the manufacturing, clinical development, commercialization, and market acceptance of the Company’s therapeutic candidates; (v) the Company’s ability to successfully market Donnatal® and EnteraGam®, (vi) the Company’s ability to establish and maintain corporate collaborations; (vii) the Company's ability to acquire products approved for marketing in the U.S. that achieve commercial success and build its own marketing and commercialization capabilities; (viii) the interpretation of the properties and characteristics of the Company’s therapeutic candidates and of the results obtained with its therapeutic candidates in research, preclinical studies or clinical trials; (ix) the implementation of the Company’s business model, strategic plans for its business and therapeutic candidates; (x) the scope of protection the Company is able to establish and maintain for intellectual property rights covering its therapeutic candidates and its ability to operate its business without infringing the intellectual property rights of others; (xi) parties from whom the Company licenses its intellectual property defaulting in their obligations to the Company; and (xii) estimates of the Company’s expenses, future revenues capital requirements and the Company’s needs for additional financing; (xiii) competitive companies and technologies within the Company’s industry. More detailed information about the Company and the risk factors that may affect the realization of forward-looking statements is set forth in the Company's filings with the Securities and Exchange Commission (SEC), including the Company's Annual Report on Form 20-F filed with the SEC on February 23, 2017. All forward-looking statements included in this Press Release are made only as of the date of this Press Release. We assume no obligation to update any written or oral forward-looking statement unless required by law.

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