News Article | February 27, 2017
BASEL, Switzerland--(BUSINESS WIRE)--DIA, (founded as the Drug Information Association) announced critical workshops to be held at the 2017 DIA EuroMeeting on March 29-31, 2017 at the SECC, Glasgow. The goal of the annual DIA EuroMeeting has always been to stimulate solutions by bringing together diverse stakeholder perspectives on issues affecting drug development in Europe. Of particular importance for 2017, is the future impact of the Brexit decision across the European regulatory environment. With the European Medicines Agency (EMA) and over 1,200 QPPVs currently operating within the UK, practical solutions are needed for those roles that must legally reside in the EU. Critical stakeholders will share their perspectives on the path forward. DIA EuroMeeting aims to bring together key healthcare stakeholder groups, such as industry, regulators, pharmacovigilance, and patients to discuss and share insights on practical solutions as well as longer term impacts of regulatory changes that need to be considered for both EU and UK citizens. The 2017 EuroMeeting theme “Translational Health Care: From Bench to Bedside – and Back” also demonstrates the importance of incorporating learnings from actual patients into R&D. A new “DIAmond Session” introduces the critical theme of facilitating early patient access to innovative medicines, while the patient voice is directly incorporated in over a dozen sessions. “Leaders across the pharmaceutical industry and regulatory agencies recognize the often conflicting goals of cost containment and accelerated access to new treatments,” said Holger Adelmann, MD, PhD, Senior Vice President & Managing Director, DIA EMEA. “The path forward is achieved by multi-stakeholder collaboration, and DIA’s EuroMeeting continues to be a destination for sparking these necessary conversations.” DIA (founded as the Drug Information Association) provides is a global, neutral forum where stakeholders can openly and freely exchange knowledge information and insights beyond boundaries to advance innovation in health care product development and lifecycle management globally. DIA is an international, nonprofit, multidisciplinary member association that provides health care product development professionals a neutral and transparent forum for collaboration and the exchange of insights to improve health globally through the advancement of lifesaving medicines and technologies. DIA builds knowledge through, learning solutions (digital and in person training), conferences and insights in the areas of, Regulatory Science, Translational Medicine, Patient Engagement and Value and Access for professionals in the pharmaceutical, biotechnology, and medical device communities. DIA is based in Washington, DC (US) with regional offices representing the Americas (Horsham, PA, US); Europe, the Middle East and Africa, (Basel, Switzerland); and Asia (Beijing and Shanghai, China; Mumbai, India; and Tokyo, Japan). For more information, visit www.DIAglobal.org or connect with us on Twitter, LinkedIn, Facebook, and Instagram.
News Article | April 24, 2017
(Georgia State University) Researchers from Georgia State University's Center for Molecular & Translational Medicine have received a four-year, $2.8 million federal grant to study diabetic cardiomyopathy, diabetes-related changes in the structure and function of the heart muscle.
News Article | May 2, 2017
NEW YORK--(BUSINESS WIRE)--Heritage Provider Network (HPN), in partnership with Crain’s Custom Studio – a division of Crain’s New York Business – will honor the 25 finalists of the second Heritage Healthcare Innovation Awards on Monday, May 22nd, for transforming access to and quality of affordable healthcare in the New York metropolitan area. The exclusive celebratory luncheon will unveil the five winners of this year’s awards: Heritage Innovation in Healthcare Delivery Award; Heritage Healthcare Leadership Award; Heritage Healthcare Organizational Leadership Award; Heritage Innovators in Healthcare Awards; and Heritage Research Investigators in Translational Medicine Award. The finalists include: The luncheon will be held on Monday, May 22nd, at 11:30 AM – 2:00 PM at The New York Athletic Club in New York City. For more information, please visit: www.crainsnewyork.com/heritage Heritage Provider Network, Inc. (HPN) is one of the most experienced physician organization leaders of accountable care and continuous value based healthcare delivery improvements. Developing and managing coordinated, patient-doctor centric, integrated health care systems that offers some of the strongest solutions for the future of health, care and cost in the United States. HPN and its affiliates operate in New York, California, Arizona and Missouri providing high quality, cost effective healthcare with over one million patient members and are dedicated to quality, affordable health care, and putting patients' wellness first. (www.heritageprovidernetwork.com) Crain's New York Business provides news, information and connections on all facets of New York through the prism of business. Crain’s is the leading source of information on the New York economy, the companies and industries that operate here, and connections between government and industry. Crain’s publishes daily news coverage on crainsnewyork.com, weekly coverage in print, and two specialized online daily reports—Insider and Pulse—providing scoops and inside information on politics and health care. Readers come to Crain's for in-depth coverage of the many industries that make up the fabric of New York's business community.
News Article | May 4, 2017
LYON, France--(BUSINESS WIRE)--POXEL SA (Euronext – POXEL - FR0012432516), a biopharmaceutical company focused on the development of innovative drugs to treat metabolic diseases, including type 2 diabetes, announced today positive top line Phase 2b data results for Imeglimin for the treatment of type 2 diabetes in Japan. The randomized, double-blind, placebo-controlled study of Imeglimin administered twice-daily for 24 weeks, demonstrated dose-dependent efficacy on two key measures of diabetes control in 299 Japanese patients. The trial achieved statistical significance (p<0.0001) for its primary endpoint of glycated hemoglobin A1c reduction versus placebo in all treatment groups at 24 weeks. In the study, hemoglobin A1c reduction was 0.52%, 0.94% and 1.00% for the 500 mg, 1000 mg and 1500 mg dose twice-daily, respectively. The level of reduction of hemoglobin A1c for Imeglimin was even more pronounced in the Japanese Phase 2b data than what has previously been shown in the U.S. and EU Phase 2b data. For the study’s key secondary endpoint of a decrease in Fasting Plasma Glucose (FPG), the top two Imeglimin doses of 1000 mg and 1500 mg achieved statistical significance (p<0.0001) versus placebo at 24 weeks. Analyses of data for the additional secondary endpoints are ongoing. In this study, Imeglimin was shown to be safe and well tolerated and the adverse event profile was consistent to what was observed in the U.S. and EU Phase 1 and 2 programs. The Company anticipates meeting with the Pharmaceuticals and Medical Devices Agency in Japan during the third quarter, and pending feedback from the meeting, the Company plans to be in the position to advance Imeglimin into a Phase 3 program in Japan during the fourth quarter of 2017. "The strong efficacy of Imeglimin observed in this study suggests that its innovative mechanism of action may play an important role in the treatment of type 2 diabetes and could be particularly well-suited for Japanese patients,” said Pascale Fouqueray, MD, PhD, Executive Vice President, Early Development & Translational Medicine of Poxel. “Imeglimin has been successfully studied in over 1,200 subjects and has shown a differentiated product profile combined with favorable safety, and we believe that it has the potential to address the large and growing needs of the type 2 diabetes market.” “We are very pleased with these results and are actively preparing for the Imeglimin Phase 3 program in Japan. The Phase 3 program is anticipated to include 3 pivotal trials as well as non-pivotal studies in specific patient populations to further differentiate Imeglimin from other approved therapies in Japan,” said Christophe Arbet-Engels, MD, PhD, MBA, Chief Medical Officer and Executive Vice President, Late Development & Medical Affairs of Poxel. “Diabetes is a growing health concern in Asia and with these data results we are encouraged that Imeglimin could become an innovative new treatment option for Japanese patients to manage their type 2 diabetes.” "This is a significant milestone for Poxel. Japan is a key focus and is an integral part of our business strategy, especially with the unique treatment paradigm for innovative therapies. In Japan, we believe Imeglimin may be a prime candidate for first-line treatment as monotherapy and as an add-on to other glucose lowering therapies for the treatment of patients with type 2 diabetes,” said Thomas Kuhn, CEO of Poxel. “Japan represents the second largest single market for type 2 diabetes and is expected to grow to approximately $6 billion in annual sales in 2020*. Asia, in broader terms, is considered the most important geographic location with regards to treating the diabetes pandemic in the future." Poxel anticipates presenting the full data results of the Phase 2b study in Japanese patients at scientific meetings during the second half of 2017. Poxel will host an investor conference call today to discuss the Phase 2b data results at 7 pm Central European Summer Time (1 pm Eastern Daylight Time). To participate in the call, please use the dial-in numbers below. About Imeglimin Imeglimin is the first clinical candidate in a new chemical class of oral agents called the Glimins. Imeglimin has a unique mechanism of action (MOA) that targets mitochondrial bioenergetics. Imeglimin acts on the three main target organs involved in glucose homeostasis: the liver, muscle, and the pancreas. This MOA has the potential for glucose lowering benefits, as well as the potential to prevent endothelial dysfunction, which can provide protective effects on micro- and macro-vascular defects induced by diabetes. The additional protective effect on beta-cell survival and function may lead to a delay in disease progression. This unique mode of action compared to existing treatments for type 2 diabetes makes Imeglimin a prime candidate in all stages of the current anti-diabetic treatment paradigm, including monotherapy or as an add-on to other glucose lowering therapies for the treatment of patients with type 2 diabetes. About Poxel SA Poxel uses its development expertise in metabolism to advance a pipeline of drug candidates focused on the treatment of metabolic disorders, including type 2 diabetes. We have successfully completed a Phase 2 clinical program for our first-in-class lead product, Imeglimin, which targets mitochondrial dysfunction, in the U.S., EU and Japan. Our second program, PXL770, a direct AMPK activator, is in Phase 1 development. We intend to generate further growth through strategic partnerships and pipeline development. (Euronext: POXEL, www.poxel.com)
News Article | April 27, 2017
Since its inception, MMAAP foundation has awarded over 40 Fellowship and Project grants to support the work of exceptional physician scientists and investigators with the vision, drive and dedication to find new and innovative ways towards advancements in the targeted medical fields. These outstanding award recipients represent more than 20 prestigious Chinese medical institutions including Peking Union Medical College Hospital, Xijing Hospital, the Fourth Military Medical University, Peking University Institute of Hematology, West China Hospital, Sichuan University, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, and others. "The visionary leadership of MMAAP Foundation Chairman and Founder, Howard P. Milstein, has brought together and funded exchanges between outstanding researchers, medical talent, and institutions in these regions," said Sean X. Leng, MD, PhD, President of MMAAP Foundation. "The 2017 recipients are among the most talented investigators in their fields and our support of their work is vital to both furthering medical research and strengthening relations between the U.S. and China." Grant applications were evaluated through a two-step peer review process according to the National Institute of Health standard. Panels of Chinese and U.S. experts in their respective fields jointly reviewed all proposals, and finalists were submitted for approval by MMAAP Foundation. The U.S. panels in Geriatrics, Skin Disease, Hematology, Reproductive Medicine, and Translational Medicine include members of the American Geriatrics Society, Medical Advisory Committee of American Skin Association, New York Blood Center, Jones Foundation for Reproductive Medicine, as well as members of other leading U.S. institutions in each field. The mission of Milstein Medical Asian American Partnership Foundation (MMAAP Foundation) is to improve world health by developing mutually beneficial partnerships between the U.S. and China, as well as greater Asia. Working with some of the premier health organizations in the world, MMAAP Foundation brings together and funds exchanges among the best research, medical talent, and institutions in the regions. This strategy is a high priority for MMAAP Foundation's founder Howard P. Milstein. MMAAP Foundation is a 501(c) (3) non-profit organization. For more than 50 years, the Milstein family has been actively involved in health-related and medical philanthropy. MMAAP Foundation builds upon this distinguished history in five areas: Senior Healthcare, Skin Disease and Melanoma, Reproductive Biology, Blood Research, and Translational Medicine. MMAAP Foundation works in close collaboration with other medical organizations supported by the Milstein family, including American Skin Association, Milstein Melanoma Research Program at The Rockefeller University, Howard and Georgeanna Jones Foundation for Reproductive Medicine, New York Blood Center, and the Program for Translational Chemical Biology at New York-Presbyterian Hospital/Weill Cornell Medical Center. For more information, please visit MMAAP Foundation's website at www.mmaapf.org. To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/milstein-medical-asian-american-partnership-foundation-announces-2017-fellowship-and-project-awards-300447740.html
News Article | March 2, 2017
REDWOOD CITY, Calif., March 02, 2017 (GLOBE NEWSWIRE) -- OncoMed Pharmaceuticals Inc. (NASDAQ:OMED) will present new data related to its clinical and preclinical immuno-oncology and anti-cancer stem cell therapeutic candidates in a total of six presentations at the upcoming American Association for Cancer Research (AACR) Meeting to be held April 1-5, 2017 in Washington, DC. Among the presentations will be three posters detailing preclinical data for OncoMed’s novel anti-TIGIT (OMP-313M32) immuno-oncology therapeutic candidate. These will be the first data that the company has shared publicly for its anti-TIGIT antibody program. New data will also be presented on biomarker research associated with the Phase 1b portion of OncoMed’s tarextumab (anti-Notch2/3, OMP-59R5) clinical trial in small cell lung cancer and OncoMed’s preclinical GITRL-Fc trimer (OMP-336B11) program. In addition, xenograft data will be presented for anti-RSPO3 (OMP-131R10) in combination with taxane chemotherapy in colorectal cancer. The following abstracts have been selected for presentation by OncoMed scientists: Sunday, April 2, 2017 1:00 PM – 5:00 PM Title: Pharmacodynamic biomarkers for anti-TIGIT treatment and prevalence of TIGIT expression in multiple solid tumor types Presenting author: Fiore Cattaruzza, Pharm. D., Ph.D., Senior Scientist II, Translational Medicine Abstract Number: 599 Session: T-cell Immunity to Cancer: New Progress Location: Poster section 26; Poster board 3 Monday, April 3, 2017 8:00 AM - Noon Title: Antibody against TIGIT (T-cell immunoreceptor with Ig and ITIM domains) induces anti-tumor immune response and generates long-term immune memory Presenting author: Angie Inkyung Park, Ph.D., Senior Director Immunotherapy Abstract Number: 2003 Session: Tumor Microenvironment Location: Poster section 44; Poster board 18 Title: Circulating Tumor Cells (CTCs) in patients with extensive-stage small cell lung cancer and their association with clinical outcome Abstract number: 1727 Presenting author: Chun Zhang, Ph.D., Director, Translational Medicine Session: Liquid Biopsies 1: Circulating Tumor Cells Location: Poster section 30; Poster board 17 Monday, April 3, 2017 1:00 PM – 5:00 PM Title: Anti-TIGIT induces T cell mediated anti-tumor immune response and combines with immune checkpoint inhibitors to enhance strong and long term anti-tumor immunity Abstract number: 2612 Presenting author: Minu Srivastava, Ph.D., Senior Scientist II Session: Checkpoints 2: Small Molecule Inhibitors (Note: anti-TIGIT is a monoclonal antibody) Location: Poster section 25; Poster board 1 Wednesday, April 5, 2017 8:00 AM - Noon Title: Prevalence of GITR expression and pharmacodynamic (PD) biomarkers in syngeneic tumor models treated by a GITR agonist (GITRL-Fc) Abstract number: 5621 Presenting author: Min Wang, Ph.D., Director, Translational Medicine Session: Immune Checkpoints and Immunosurveillance Location: Poster section 25; Poster board 23 About OncoMed Pharmaceuticals OncoMed Pharmaceuticals is a clinical-stage biopharmaceutical company focused on discovering and developing novel anti-cancer stem cell and immuno-oncology therapeutics. OncoMed has internally discovered a broad pipeline of investigational drugs intended to address the fundamental biology driving cancer’s growth, resistance, recurrence and metastasis. Demcizumab (anti-DLL4, OMP-21M18), tarextumab (anti-Notch2/3, OMP-59R5), anti-DLL4/VEGF bispecific (OMP-305B83), vantictumab (anti-FZD7, OMP-18R5), ipafricept (FZD8-Fc, OMP-54F28), anti-RSPO3 (OMP-131R10) and anti-TIGIT (OMP-313M32) are part of the company’s strategic alliances with Celgene Corporation, Bayer Pharma AG and GlaxoSmithKline (GSK). OncoMed is independently developing brontictuzumab (anti-Notch1, OMP-52M51) and GITRL-Fc (OMP-336B11), as well as continuing to pursue new drug discovery research efforts. For further information about OncoMed Pharmaceuticals, please see www.oncomed.com.
News Article | March 2, 2017
A new study published this month in STEM CELLS Translational Medicine indicates that treating heart patients with mesenchymal stem cells (MSCs) does not increase their risk of irregular heart beat (arrhythmia). In fact, the MSCs had the opposite effect and showed promise of improving the condition. “This could be an important breakthrough for many heart patients, as proarrhythmia – which is a new or more frequent occurrence of pre-existing arrhythmia – unfortunately can be a side effect of some of the drugs we’re using to treat these patients,” said the study’s lead author, Raul Mitrani, M.D., of the University of Miami School of Medicine’s Division of Cardiology (Miami, Florida). Arrhythmia is a common condition resulting when electrical impulses in the heart do not work properly, causing the heart to beat either too fast, too slow or erratically. This in turn interferes with blood flow throughout the body and can potentially damage or shut down organs. While some experience no symptoms and their arrhythmia is harmless, in others it can be life threatening. Treatments include anti-arrhythmic drugs; implantable devices such as a pacemaker; surgery; or catheter ablation (a procedure that uses radiofrequency energy to destroy a small area of heart tissue that is causing the off-kilter beats). As more studies are showing the potential of stem cells to repair damage caused by heart disease, Dr. Mitrani and his colleagues at UM wondered whether the stem cells – specifically MSCs, which are 'adult' stem cells that can produce more than one type of specialized cell of the body – would follow the path of some of the anti-arrhythmia drugs and worsen the condition. Previous studies had indicated that perhaps was the case with certain other types of stem cells, but no studies had focused on MSCs. To find the answer, they analyzed the results of 88 patients enrolled in two clinical trials testing the potential of MSCs in treating ischemic cardiomyopathy. This is a common condition in which the heart's ability to pump blood is decreased because its main pumping chamber, the left ventricle, is enlarged, dilated and weak. The patients had an average age of 61 years and were divided into groups treated with either MSCs, bone marrow stem cells (BMCs) or placebo. A year after their treatments, those who received MSCs all showed no signs of arrhythmia. “We were encouraged by what we saw,” Dr. Mitrani said. “Even better, in a group of patients with low ventricular ectopy burden – what some call ‘heart hiccups’ or ‘skipped beats’ – there were definite signs of improvement while in the BMC and placebo groups, no similar signal for improvement was noted. “This leads us to believe that prospective studies might clarify the role of MSCs to reduce ventricular arrhythmias.” “By combining data from two studies, the authors were able to study this question in one of the largest groups of patients to date,” said Anthony Atala, Editor-in-Chief of STEM CELLS Translational Medicine and director of the Wake Forest Institute for Regenerative Medicine. “These findings are important because they emphasize the need for further large prospective studies to evaluate the anti-arrhythmic potential of mesenchymal and other newer cell-based therapies.” The full article, “Effects of Transendocardial Stem Cell Injection on Ventricular Proarrhythmia in Patients with Ischemic Cardiomyopathy: Results from the POSEIDON and TAC-HFT Trials,” can be accessed at: http://onlinelibrary.wiley.com/doi/10.1002/sctm.16-0328/full. About STEM CELLS Translational Medicine: STEM CELLS Translational Medicine (SCTM), published by AlphaMed Press, is a monthly peer-reviewed publication dedicated to significantly advancing the clinical utilization of stem cell molecular and cellular biology. By bridging stem cell research and clinical trials, SCTM will help move applications of these critical investigations closer to accepted best practices. About AlphaMed Press: Established in 1983, AlphaMed Press with offices in Durham, NC, San Francisco, CA, and Belfast, Northern Ireland, publishes two other internationally renowned peer-reviewed journals: STEM CELLS® (http://www.StemCells.com), celebrating its 35th year, is the world's first journal devoted to this fast paced field of research. The Oncologist® (http://www.TheOncologist.com), also a monthly peer-reviewed publication, entering its 22nd year, is devoted to community and hospital-based oncologists and physicians entrusted with cancer patient care. All three journals are premier periodicals with globally recognized editorial boards dedicated to advancing knowledge and education in their focused disciplines.
News Article | February 28, 2017
Silicon Kinetics Inc., the supplier of 3D nano-porous silicon biosensors and instruments for sensitive, label-free biomolecular interaction analysis, has announced collaborations with Biosys Technologies, Tokyo University and St. Marianna University, School of Medicine in Japan. The collaborators expect rapid and effective screening and ranking of inhibitors, thanks to the novel inline MIK-MS approach pioneered by Silicon Kinetics. MIK-MS (Molecular Interaction Kinetics - Mass Spectrometry) enables researchers to kinetically rank target molecules by affinity capture on silicon biosensor surfaces, then elute the candidate inhibitors to an inline LC- ESI mass spectrometer for identification and quantitation. The 3D surface of SKi Sensors captures more than 100 times the quantities on planar surfaces, making possible this MIK-MS workflow, previously not viable on planar biosensors such as those used in SPR (Surface Plasmon Resonance). The higher loading capacity of 3D SKi Sensors allows the quantification of kinetics, even when the ratio of the molecular weights of the interacting molecules is high (as in the case of a large protein interacting with a small molecule), or when a drug candidate needs to be highly diluted for solubility, or when the biomolecular interactions are weak. MIK-MS technology thus brings new and effective screening capabilities to PPI (Protein Pump Inhibitor), FBDD (Fragment-Based Drug Discovery) and biomarker discovery. Biosys Technologies, Inc., is an application development and system integration company based in Tokyo, serving the biotech and pharma markets in Japan. Through its clinical and technological alliances with major medical schools and hospitals, Biosys has access to tissue and blood samples and cancer databases. Silicon Kinetics and Biosys have agreed to work with lung cancer experts at Tokyo University and St. Marianna University, such as Dr. Kawamura and Prof. Nishimura, to study the progression of lung cancer in non-smoking adults, as well as potential treatments based on the principles of personalized medicine. “The novel MIK-MS approach forms the basis for state-of-the art-screening, as it not only enables novel protein identification but also gives information about protein interactions, signal pathways and mutations in conjunction with databases and related informatics,” said Prof. Toshihide Nishimura, the Director of the Translational Medicine Informatics, St. Marianna University School of Medicine. About Silicon Kinetics: Silicon Kinetics Inc. is the developer and supplier of the world’s first nano-porous silicon biosensor for analyzing biomolecular interactions, including antibody-antigen and protein-small molecule interactions. Unlike the planar surface of biosensors based on SPR, the 3D volume of SKi Sensors, interrogated by white-light interferometry in the SKi Pro line of instruments, offers researchers higher sensitivities in traditional biomolecular interaction analysis and larger amounts of captured molecules in MIK-MS (Molecular Interaction Kinetics - Mass Spectrometry) applications. For MIK-MS, Silicon Kinetics offers SKi Bridge, which acts as a fraction collector and timing synchronization tool, directly connected to any mass spectrometer. More information can be found at http://www.siliconkinetics.com.
News Article | March 1, 2017
It's what's missing in the tumor genome, not what's mutated, that thwarts treatment of metastatic melanoma with immune checkpoint blockade drugs, researchers at The University of Texas MD Anderson Cancer Center report in Science Translational Medicine. Whole exome sequencing of tumor biopsies taken before, during and after treatment of 56 patients showed that outright loss of a variety of tumor-suppressing genes with influence on immune response leads to resistance of treatment with both CTLA4 and PD1 inhibitors. The team's research focuses on why these treatments help 20-30 percent of patients -- with some complete responses that last for years - but don't work for others. Their findings indicate that analyzing loss of blocks of the genome could provide a new predictive indicator. "Is there a trivial or simple (genomic) explanation? There doesn't seem to be one," said co-senior author Andrew Futreal, Ph.D., professor and chair of Genomic Medicine and co-leader of MD Anderson's Moon Shots Program™. "There's no obvious correlation between mutations in cancer genes or other genes and immune response in these patients." "There are, however, pretty strong genomic copy loss correlates of resistance to sequential checkpoint blockade that also pan out for single-agent treatment," Futreal said. Doctoral candidate Whijae Roh, co-lead author, Futreal, and co-senior author Jennifer Wargo, M.D., associate professor of Surgical Oncology and Genomic Medicine, and colleagues analyzed the genomic data for non-mutational effects. "We found a higher burden of copy number loss correlated to response to immune checkpoint blockade and to lower immune scores, a measure of immune activation in the tumor's microenvironment," said Roh, a graduate student in the University of Texas MD Anderson UTHealth Graduate School of Biomedical Sciences. "We also found copy loss has an effect that is independent of mutational load in the tumors." Melanoma tumors with larger volumes of genetic alterations, called mutational load, provide more targets for the immune system to detect and are more susceptible to checkpoint blockade, although that measure is not conclusive alone. "Combining mutational load and copy number loss could improve prediction of patient response," Wargo said. When the team stratified patients in another data set of patients by whether they had high or low copy loss or high or low mutational load, they found that 11 of 26 patients with high mutational load and low copy loss had a clinical benefit, while only 4 or 26 with low mutational load and high copy loss benefited from treatment. In the trial, patients were treated first with the immune checkpoint inhibitor ipilimumab, which blocks a brake called CTLA4 on T cells, the immune system's specialized warriors, freeing them to attack. Patients whose melanoma did not react then went on to anti-PD1 treatment (nivolumab), which blocks a second checkpoint on T cells. Biopsies were taken, when feasible, before, during and after treatment for molecular analysis to understand response and resistance. To better understand the mechanisms at work, the team analyzed tumor genomes for recurrent copy loss among 9 tumor biopsies from patients who did not respond to either drug and had high burden of copy number loss. They found repeated loss of blocks of chromosomes 6, 10 and 11, which harbor 13 known tumor-suppressing genes. Analysis of a second cohort of patients confirmed the findings, with no recurrent tumor-suppressor loss found among any of the patients who had a clinical benefit or long-term survival after treatment. Ipilimumab sometimes wins when it fails The researchers also found a hint that treatment with ipilimumab, even if it fails, might prime the patient's immune system for successful anti-PD1 treatment. The team analyzed the genetic variability of a region of the T cell receptors, a feature of T cells that allows them to identify, attack and remember an antigen target found on an abnormal cell or an invading microbe. They looked for evidence of T cell "clonality," an indicator of active T cell response. Among eight patients with longitudinal samples taken before treatment with both checkpoint types, all three who responded to anti-PD1 therapy had shown signs of T cell activation after anti-CTLA treatment. Only one of the five non-responders had similar indicators of T cell clonality. "That's evidence that anti-CTLA4 in some cases primes T cells for the next step, anti-PD1 immunotherapy. It's well known that if you don't have T cells in the tumor, anti-PD1 won't do anything, it doesn't bring T cells into the tumor," Futreal says. Overall, they found that T cell clonality predicts response to PD1 blockade but not to CTLA-4 blockade. "Developing an assay to predict response will take an integrated analysis, thinking about genomic signatures and pathways, to understand the patient when you start therapy and what happens as they begin to receive therapy," Wargo said. "Changes from pretreatment to on-therapy activity will be important as well." The Science Translational Medicine paper is the third set of findings either published or presented at scientific meetings by the team, which is led by Futreal and Wargo, who also is co-leader of the Melanoma Moon Shot™. Immune-monitoring analysis showed that presence of immune infiltrates in a tumor after anti-PD1 treatment begins is a strong predictor of success. They also presented evidence that the diversity and composition of a patient's gut bacteria also affects response to anti-PD1 therapy. The serial biopsy approach is a hallmark of the Adaptive Patient-Oriented Longitudinal Learning and Optimization™ (APOLLO) platform of the Moon Shots Program™, co-led by Futreal that systematically gathers samples and data to understand tumor response and resistance to treatment over time. The Moon Shots Program™ is designed to reduce cancer deaths by accelerating development of therapies, prevention and early detection from scientific discoveries. Futreal holds the The Robert A. Welch Distinguished University Chair in Chemistry at MD Anderson. Co-authors with Roh, Futreal and Wargo are co-first authors Pei-Ling Chen, M.D., of Genomic Medicine and Pathology, and Alexandre Reuben, Ph.D., of Surgical Oncology; also Christine Spencer, Feng Wang, Ph.D., Zachary Cooper, Ph.D., Curtis Gumbs, Latasha Little, Qing Chang, Wei-Shen Chen, M.D., and Jason Roszik, Ph.D., of Genomic Medicine; Michael Tetzlaff, Ph.D., M.D., and Victor Prieto, M.D., Ph.D., of Pathology; Peter Prieto, M.D., Vancheswaran Gopalakrishnan, Jacob L. Austin-Breneman, Hong Jiang, Ph.D., and Jeffrey Gershenwald, M.D., of Surgical Oncology; John Miller, Ph.D., Oncology Research for Biologics and Immunotherapy Translation (ORBIT); Sangeetha Reddy, M.D., Division of Cancer Medicine; Khalida Wani, Ph.D., Mariana Petaccia De Macedo, M.D., Ph.D., Eveline Chen, and Alexander Lazar, M.D., Ph.D., of Translational Molecular Pathology; Michael Davies, M.D., Ph.D., Hussein Tawbi, M.D., Ph.D., Patrick Hwu, M.D., Wen-Jen Hwu, M.D., Ph.D., Adi Diab, M.D., Isabella Glitza, M.D., Ph.D., Sapna Patel, M.D., Scott Woodman, M.D., Ph.D., and Rodabe Amaria, M.D., of Melanoma Medical Oncology; Jianhua Hu, Ph.D., of Biostatistics; Padmanee Sharma, M.D., Ph.D., and James Allison, Ph.D., of Immunology; Lynda Chin, M.D., University of Texas System; and Jianhua Zhang Ph.D., of the Institute for Applied Cancer Science. Wargo, Sharma and Allison are all members of the Parker Institute for Cancer Immunotherapy. The research was funded by MD Anderson's Melanoma Moon Shot™, the Melanoma Research Alliance Team Science Award, the John G. and Marie Stella Kenedy Memorial Foundation, the University of Texas System STARS program; the Cancer Prevention and Research Institute of Texas; the American Society of Clinical Oncology; Conquer Cancer Foundation; the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation; and grants from the National Cancer Institute of the National Institutes of Health (U54CA163125, 1K08CA160692-01A1, T32CA009599, NIH T32 CA009666, R01 CA187076-02) and MD Anderson's Institutional Tissue Bank (2P30CA016672) Spencer and Gopalakrishnan are graduate students in The University of Texas Health Science Center at Houston School of Public Health.
News Article | March 2, 2017
(Philadelphia, PA) - Mitochondria - the energy-generating powerhouses of cells - are also a site for oxidative stress and cellular calcium regulation. The latter two functions have long been suspected of being linked mechanistically, and now new research at the Lewis Katz School of Medicine at Temple University (LKSOM) shows precisely how, with the common connection centering on a protein complex known as the mitochondrial Ca2+ uniporter (MCU). "MCU had been known for its part in driving mitochondrial calcium uptake for cellular energy production, which protects cells from bioenergetic crisis, and for its role in eliciting calcium overload-induced cell death," explained senior investigator on the study, Muniswamy Madesh, PhD, Professor in the Department of Medical Genetics and Molecular Biochemistry and Center for Translational Medicine at LKSOM. "Now, we show that MCU has a functional role in both calcium regulation and the sensing of levels of reactive oxygen species (ROS) within mitochondria." The study, published online March 2 in the journal Molecular Cell, is the first to identify a direct role for MCU in mitochondrial ROS-sensing. In previous work, Dr. Madesh and colleagues were the first to show how the MCU protein complex comes together to effect mitochondrial calcium uptake. "We know from that work, and from existing work in the field, that as calcium accumulates in mitochondria, the organelles generate increasing amounts of ROS," Dr. Madesh said. "Mitochondria have a way of dealing with that ROS surge, and because of the relationship between mitochondrial calcium uptake and ROS production, we suspected ROS-targeting of MCU was involved in that process." In the new study, Dr. Madesh and colleagues employed advanced biochemical, cell biological, and superresolution imaging to examine MCU oxidation in the mitochondrion. Critically, they discovered that MCU contains several cysteine molecules in its amino acid structure, only one of which, Cys-97, is capable of undergoing an oxidation-induced reaction known as S-glutathionylation. Structural analyses showed that oxidation-induced S-glutathionylation of Cys-97 triggers conformational changes within MCU. Those changes in turn regulate MCU activity during inflammation, hypoxia, and cardiac stimulation. They also appear to be relevant to cell survival - elimination of ROS-sensing via Cys-97 mutation resulted in persistent MCU channel activity and an increased rate of calcium-uptake, with cells eventually dying from calcium overload. Importantly, Dr. Madesh and colleagues found that S-glutathionylation of Cys-97 is reversible. "Reversible oxidation is essential to the regulation of protein function," Dr. Madesh explained. When switched on by oxidation, Cys-97 augments MCU channel activity that perpetuates cell death. Oxidation reverses when the threat has subsided. The findings could have implications for the understanding of metabolic disorders and neurological and cardiovascular diseases. "Abnormalities in ion homeostasis are a central feature of metabolic disease," Dr. Madesh said. "We plan next to explore the functional significance of ROS and MCU activity in a mouse model using genome editing technology, which should help us answer fundamental questions about MCU's biological functions in mitochondrial ROS-sensing." Other researchers involved in the study include Zhiwei Dong, Santhanam Shanmughapriya, Dhanendra Tomar, Neeharika Nemani, Sarah L. Breves, Aparna Tripathi, Palaniappan Palaniappan, Massimo F. Riitano, Alison Worth, Ajay Seelam, Edmund Carvalho, Ramasamy Subbiah, Fabia?n Jan?a, and Sudarsan Rajan, Department of Medical Genetics and Molecular Biochemistry and the Center for Translational Medicine at LKSOM; Jonathan Soboloff, Department of Medical Genetics and Molecular Biochemistry at LKSOM; Xueqian Zhang and Joseph Y. Cheung, Center for Translational Medicine at LKSOM; Naveed Siddiqui and Peter B. Stathopulos, Department of Physiology and Pharmacology, Western University, London, Ontario, Canada; Solomon Lynch and Jeffrey Caplan, Department of Biological Sciences, Delaware Biotechnology Institute, University of Delaware; Suresh K. Joseph, MitoCare Center, Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia; Yizhi Peng and Zhiwei Dong, Institute of Burn Research, Southwest Hospital, Third Military Medical University, Chongqing, People's Republic of China. The research was supported in part by National Institutes of Health grants R01GM109882, R01HL086699, R01HL119306, 1S10RR027327, P01 DA037830, and RO1DK103558. Temple University Health System (TUHS) is a $1.6 billion academic health system dedicated to providing access to quality patient care and supporting excellence in medical education and research. The Health System consists of Temple University Hospital (TUH), ranked among the "Best Hospitals" in the region by U.S. News & World Report; TUH-Episcopal Campus; TUH-Northeastern Campus; Fox Chase Cancer Center, an NCI-designated comprehensive cancer center; Jeanes Hospital, a community-based hospital offering medical, surgical and emergency services; Temple Transport Team, a ground and air-ambulance company; and Temple Physicians, Inc., a network of community-based specialty and primary-care physician practices. TUHS is affiliated with the Lewis Katz School of Medicine at Temple University. The Lewis Katz School of Medicine (LKSOM), established in 1901, is one of the nation's leading medical schools. Each year, the School of Medicine educates approximately 840 medical students and 140 graduate students. Based on its level of funding from the National Institutes of Health, the Katz School of Medicine is the second-highest ranked medical school in Philadelphia and the third-highest in the Commonwealth of Pennsylvania. According to U.S. News & World Report, LKSOM is among the top 10 most applied-to medical schools in the nation. Temple Health refers to the health, education and research activities carried out by the affiliates of Temple University Health System (TUHS) and by the Katz School of Medicine. TUHS neither provides nor controls the provision of health care. All health care is provided by its member organizations or independent health care providers affiliated with TUHS member organizations. 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