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  • Generation of Effector Memory T Cell–Based Mucosal and Systemic Immunity with Pulmonary Nanoparticle Vaccination | Science Translational Medicine
    Beth Israel Deaconess Medical Center Boston MA 02215 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Maria H Foley Department of Biological Engineering Massachusetts Institute of Technology MIT Cambridge MA 02139 USA Koch Institute for Integrative Cancer Research MIT Cambridge MA 02139 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dan H Barouch Ragon Institute of MGH MIT and Harvard Boston MA 02139 USA Center for Virology and Vaccine Research Beth Israel Deaconess Medical Center Boston MA 02215 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Darrell J Irvine Department of Biological Engineering Massachusetts Institute of Technology MIT Cambridge MA 02139 USA Koch Institute for Integrative Cancer Research MIT Cambridge MA 02139 USA Department of Materials Science and Engineering MIT Cambridge MA 02139 USA Howard Hughes Medical Institute Chevy Chase MD 20815 USA Ragon Institute of MGH MIT and Harvard Boston MA 02139 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the abstract View Full Text As a service to the community AAAS Science has made this article free with registration Username Enter your Sciencemag org username Password Enter the password that accompanies your username Forgot your username or password Log in Register for Free Join Subscribe Recommend a subscription to your library Help for librarians Abstract Many pathogens infiltrate the body and initiate infection via mucosal surfaces Hence eliciting cellular immune responses at mucosal portals of entry is of great interest for vaccine development against mucosal pathogens We describe a pulmonary vaccination strategy combining Toll like receptor TLR agonists with antigen carrying lipid nanocapsules interbilayer crosslinked multilamellar vesicles ICMVs which elicit high frequency long lived antigen specific effector memory T cell responses at multiple mucosal sites Pulmonary immunization using protein or peptide loaded ICMVs combined with two TLR agonists polyinosinic polycytidylic acid polyI C and monophosphoryl lipid A was safe and well tolerated in mice and led to increased antigen transport to draining lymph nodes compared to equivalent subcutaneous vaccination This response was mediated by the vast number of antigen presenting cells APCs in the lungs Nanocapsules primed 13 fold more T cells than did equivalent soluble vaccines elicited increased expression of mucosal homing integrin α 4 β 7 and generated long lived T cells in both the lungs and distal for example vaginal mucosa strongly biased toward an effector memory T EM phenotype These T EM responses were highly protective in both therapeutic tumor and prophylactic viral vaccine settings Together these data suggest that targeting cross presentation promoting particulate vaccines to the APC rich pulmonary mucosa can promote robust T cell responses for protection of mucosal surfaces Copyright 2013 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol

    Original URL path: http://stm.sciencemag.org/content/5/204/204ra130 (2016-02-10)
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  • Transepithelial Transport of Fc-Targeted Nanoparticles by the Neonatal Fc Receptor for Oral Delivery | Science Translational Medicine
    author on PubMed Search for this author on this site Robert Langer Department of Chemical Engineering Massachusetts Institute of Technology Cambridge MA 02139 USA The David H Koch Institute for Integrative Cancer Research Cambridge MA 02139 USA MIT Harvard Center for Cancer Nanotechnology Excellence Cambridge MA 02139 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Omid C Farokhzad Laboratory of Nanomedicine and Biomaterials Department of Anesthesiology Brigham and Women s Hospital Harvard Medical School Boston MA 02115 USA MIT Harvard Center for Cancer Nanotechnology Excellence Cambridge MA 02139 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the abstract View Full Text As a service to the community AAAS Science has made this article free with registration Username Enter your Sciencemag org username Password Enter the password that accompanies your username Forgot your username or password Log in Register for Free Join Subscribe Recommend a subscription to your library Help for librarians Abstract Nanoparticles are poised to have a tremendous impact on the treatment of many diseases but their broad application is limited because currently they can only be administered by parenteral methods Oral administration of nanoparticles is preferred but remains a challenge because transport across the intestinal epithelium is limited We show that nanoparticles targeted to the neonatal Fc receptor FcRn which mediates the transport of immunoglobulin G antibodies across epithelial barriers are efficiently transported across the intestinal epithelium using both in vitro and in vivo models In mice orally administered FcRn targeted nanoparticles crossed the intestinal epithelium and reached systemic circulation with a mean absorption efficiency of 13 7 hour compared with only 1 2 hour for nontargeted nanoparticles In addition targeted nanoparticles containing insulin as a model nanoparticle based therapy for diabetes were orally administered at a clinically relevant insulin dose of 1 1 U kg and elicited a prolonged hypoglycemic response in wild type mice This effect was abolished in FcRn knockout mice indicating that the enhanced nanoparticle transport was specifically due to FcRn FcRn targeted nanoparticles may have a major impact on the treatment of many diseases by enabling drugs currently limited by low bioavailability to be efficiently delivered though oral administration Copyright 2013 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol 5 Issue 213 27 November 2013 Table of Contents Article Tools Email Thank you for your interest in spreading the word about Science Translational Medicine NOTE We only request your email address so that the person you are recommending the page to knows that you wanted them to see it and that it is not junk mail We do not capture any email address Your Email Your Name Send To Enter multiple addresses on separate lines or separate them with commas You are going to email the following Transepithelial Transport of Fc Targeted Nanoparticles by

    Original URL path: http://stm.sciencemag.org/content/5/213/213ra167 (2016-02-10)
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  • Preclinical Development and Clinical Translation of a PSMA-Targeted Docetaxel Nanoparticle with a Differentiated Pharmacological Profile | Science Translational Medicine
    site Jim Wright Find this author on Google Scholar Find this author on PubMed Search for this author on this site Patricia LoRusso Find this author on Google Scholar Find this author on PubMed Search for this author on this site Philip W Kantoff Find this author on Google Scholar Find this author on PubMed Search for this author on this site Neil H Bander Find this author on Google Scholar Find this author on PubMed Search for this author on this site Christopher Sweeney Find this author on Google Scholar Find this author on PubMed Search for this author on this site Omid C Farokhzad Find this author on Google Scholar Find this author on PubMed Search for this author on this site Robert Langer Find this author on Google Scholar Find this author on PubMed Search for this author on this site Stephen Zale Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the abstract View Full Text As a service to the community AAAS Science has made this article free with registration Username Enter your Sciencemag org username Password Enter the password that accompanies your username Forgot your username or password Log in Register for Free Join Subscribe Recommend a subscription to your library Help for librarians Abstract We describe the development and clinical translation of a targeted polymeric nanoparticle TNP containing the chemotherapeutic docetaxel DTXL for the treatment of patients with solid tumors DTXL TNP is targeted to prostate specific membrane antigen a clinically validated tumor antigen expressed on prostate cancer cells and on the neovasculature of most nonprostate solid tumors DTXL TNP was developed from a combinatorial library of more than 100 TNP formulations varying with respect to particle size targeting ligand density surface hydrophilicity drug loading and drug release properties Pharmacokinetic and tissue distribution studies in rats showed that the NPs had a blood circulation half life of about 20 hours and minimal liver accumulation In tumor bearing mice DTXL TNP exhibited markedly enhanced tumor accumulation at 12 hours and prolonged tumor growth suppression compared to a solvent based DTXL formulation sb DTXL In tumor bearing mice rats and nonhuman primates DTXL TNP displayed pharmacokinetic characteristics consistent with prolonged circulation of NPs in the vascular compartment and controlled release of DTXL with total DTXL plasma concentrations remaining at least 100 fold higher than sb DTXL for more than 24 hours Finally initial clinical data in patients with advanced solid tumors indicated that DTXL TNP displays a pharmacological profile differentiated from sb DTXL including pharmacokinetics characteristics consistent with preclinical data and cases of tumor shrinkage at doses below the sb DTXL dose typically used in the clinic Copyright 2012 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol 4 Issue 128 04 April 2012 Table of Contents Article Tools Email Thank you for your interest in spreading the word about

    Original URL path: http://stm.sciencemag.org/content/4/128/128ra39 (2016-02-10)
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  • Engineering Approaches to Immunotherapy | Science Translational Medicine
    the community AAAS Science has made this article free with registration Username Enter your Sciencemag org username Password Enter the password that accompanies your username Forgot your username or password Log in Register for Free Join Subscribe Recommend a subscription to your library Help for librarians Abstract As the science of immunology grows increasingly mechanistic motivation for developing quantitative design based engineering approaches has also evolved both for therapeutic interventions and for elucidating immunological pathways in human disease This has seeded the nascent field of immunoengineering which seeks to apply engineering analyses and design approaches to problems in translational immunology For example cell engineers are creating ways to tailor and use immune cells as living therapeutics protein engineers are devising new methods of rapid antibody discovery biomaterials scientists are guiding vaccine delivery and immune cell activation with novel constructs and systems immunologists are deciphering the evolution and maintenance of T and B cell receptor repertoires which could help guide vaccine design The field is multidisciplinary and collaborative with engineers and immunologists working together to better understand and treat disease We discuss the scientific progress in this young yet rapidly evolving research area which has yielded numerous start up companies that are betting on impact in clinical and commercial translation in the near future Copyright 2012 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol 4 Issue 148 22 August 2012 Table of Contents Article Tools Email Thank you for your interest in spreading the word about Science Translational Medicine NOTE We only request your email address so that the person you are recommending the page to knows that you wanted them to see it and that it is not junk mail We do not capture any email address Your Email Your Name Send To Enter multiple addresses on separate lines or separate them with commas You are going to email the following Engineering Approaches to Immunotherapy Message Subject Your Name has forwarded a page to you from Science Translational Medicine Message Body Your Name thought you would like to see this page from the Science Translational Medicine web site Your Personal Message Send Message Download Powerpoint Print Save to my folders User Name Password Remember my user name password Submit Alerts Please log in to add an alert for this article Username Enter your Sciencemag org username Password Enter the password that accompanies your username Log in Request Permissions Citation tools Engineering Approaches to Immunotherapy By Melody A Swartz Sachiko Hirosue Jeffrey A Hubbell Science Translational Medicine 22 Aug 2012 148rv9 The rapidly evolving field of immunoengineering will bring new design strategies to clinical immunology Citation Manager Formats BibTeX Bookends EasyBib EndNote tagged EndNote 8 xml Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Share Engineering Approaches to Immunotherapy By Melody A Swartz Sachiko Hirosue Jeffrey A Hubbell Science Translational Medicine 22 Aug 2012 148rv9 The rapidly evolving field of immunoengineering will bring new design strategies to clinical immunology Permalink Copy Related Content Research

    Original URL path: http://stm.sciencemag.org/content/4/148/148rv9 (2016-02-10)
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  • Detection of Circulating Tumor DNA in Early- and Late-Stage Human Malignancies | Science Translational Medicine
    and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Swim Across America Laboratory at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hao Wang Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Brandon Luber Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Rhoda M Alani Department of Dermatology Boston University Boston MA 02215 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Emmanuel S Antonarakis Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nilofer S Azad Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alberto Bardelli Institute for Cancer Research and Treatment at Candiolo University of Torino Candiolo Turin 10060 Italy Department of Oncology University of Torino Candiolo Turin 10060 Italy FIRC Institute of Molecular Oncology IFOM Milan 20139 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Henry Brem Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site John L Cameron Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Clarence C Lee Advanced Applications and Collaborations Life Technologies Foster City CA 94404 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Leslie A Fecher Division of Oncology University of Indiana Indianapolis IN 46202 USA Indiana University Health Indianapolis IN 46202 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gary L Gallia Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peter Gibbs Ludwig Institute for Cancer Research Melbourne Branch Royal Melbourne Hospital Melbourne Victoria 3084 Australia Western Hospital Melbourne Victoria 3011 Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dung Le Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Swim Across America Laboratory at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Robert L Giuntoli Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael Goggins Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael D Hogarty Division of Oncology The Children s Hospital of Philadelphia and the Department of Pediatrics University of Pennsylvania School of Medicine Philadelphia PA 19104 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Matthias Holdhoff Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Seung Mo Hong Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Department of Pathology Asan Medical Center University of Ulsan College of Medicine Seoul 138 736 Republic of Korea Find this author on Google Scholar Find this author on PubMed Search for this author on this site Yuchen Jiao Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Hartmut H Juhl Indivumed GmbH Hamburg 20251 Germany Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jenny J Kim Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Giulia Siravegna Niguarda Cancer Center Ospedale Niguarda Ca Granda Milan 20162 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Daniel A Laheru Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Calogero Lauricella Niguarda Cancer Center Ospedale Niguarda Ca Granda Milan 20162 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael Lim Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Evan J Lipson Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Suely Kazue Nagahashi Marie Department of Neurology and Pathology School of Medicine University of Sao Paulo Sao Paulo Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site George J Netto Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kelly S Oliner Amgen Inc Thousand Oaks CA 91320 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alessandro Olivi Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Louise Olsson Department of Molecular Medicine and Surgery Karolinska Institute Stockholm SE 171 76 Sweden Find this author on Google Scholar Find this author on PubMed Search for this author on this site Gregory J Riggins Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Andrea Sartore Bianchi Niguarda Cancer Center Ospedale Niguarda Ca Granda Milan 20162 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kerstin Schmidt Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site le Ming Shih Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Sueli Mieko Oba Shinjo Department of Neurology and Pathology School of Medicine University of Sao Paulo Sao Paulo Brazil Find this author on Google Scholar Find this author on PubMed Search for this author on this site Salvatore Siena Niguarda Cancer Center Ospedale Niguarda Ca Granda Milan 20162 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dan Theodorescu University of Colorado Comprehensive Cancer Center Aurora CO 80045 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jeanne Tie Ludwig Institute for Cancer Research Melbourne Branch Royal Melbourne Hospital Melbourne Victoria 3084 Australia Find this author on Google Scholar Find this author on PubMed Search for this author on this site Timothy T Harkins Advanced Applications and Collaborations Life Technologies Foster City CA 94404 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Silvio Veronese Niguarda Cancer Center Ospedale Niguarda Ca Granda Milan 20162 Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Tian Li Wang Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jon D Weingart Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Christopher L Wolfgang Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Laura D Wood Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Dongmei Xing Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Ralph H Hruban Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Jian Wu Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA MyGenostics Inc 801 West Baltimore Street Baltimore MD 21205 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Peter J Allen Department of Surgery Memorial Sloan Kettering Cancer Center New York NY 10065 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site C Max Schmidt Departments of Surgery Biochemistry and Molecular Biology Indiana University Indianapolis IN 46202 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Michael A Choti Departments of Surgery Medicine Pathology Obstetrics and Gynecology Otolaryngology and Neurosurgery at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Victor E Velculescu Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Kenneth W Kinzler Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Bert Vogelstein Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Nickolas Papadopoulos Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Luis A Diaz Jr Ludwig Center for Cancer Genetics and Therapeutics Howard Hughes Medical Institute and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD 21231 USA Swim Across America Laboratory at Johns Hopkins Baltimore MD 21231 USA Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the abstract View Full Text Abstract The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology We used digital polymerase chain reaction based technologies to evaluate the ability of circulating tumor DNA ctDNA to detect tumors in 640 patients with various cancer types We found that ctDNA was detectable in 75 of patients with advanced pancreatic ovarian colorectal bladder gastroesophageal breast melanoma hepatocellular and head and neck cancers but in less than 50 of primary brain renal prostate or thyroid cancers In patients with localized tumors ctDNA was detected in 73 57 48 and 50 of patients with colorectal cancer gastroesophageal cancer pancreatic cancer and breast adenocarcinoma respectively ctDNA was often present in patients without detectable circulating tumor cells suggesting that these two biomarkers are distinct entities In a separate panel of 206 patients with metastatic colorectal cancers we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87 2 and its specificity was 99 2 Finally we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed Twenty three 96 of these patients developed one or more mutations in genes involved in the mitogen activated protein kinase pathway Together these data suggest that ctDNA is a broadly applicable sensitive and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer Copyright 2014 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol 6 Issue 224 19 February 2014 Table of Contents Article Tools Email Thank you for your interest in spreading the word about Science Translational Medicine NOTE We only request your email address so that the person you are recommending the page to knows that you wanted them to see it and that it is not junk mail We do not capture any email address Your Email Your Name Send To Enter multiple addresses on separate lines or separate them with commas You are going to email the following Detection of Circulating Tumor DNA in Early and Late Stage Human Malignancies Message Subject Your Name has forwarded a page to you from Science Translational Medicine Message Body Your Name thought you would like to see this page from the Science Translational Medicine web site Your Personal Message Send Message Download Powerpoint Print Save to my folders User Name Password Remember my user name password Submit Alerts Please log in to add an alert for this article Username Enter your Sciencemag org username Password Enter the password that accompanies your username Log in Request Permissions Citation tools Detection of Circulating Tumor DNA in Early and Late Stage Human Malignancies By Chetan Bettegowda Mark Sausen Rebecca J Leary Isaac Kinde Yuxuan Wang Nishant Agrawal Bjarne R Bartlett Hao Wang Brandon Luber Rhoda M Alani Emmanuel S Antonarakis Nilofer S Azad Alberto Bardelli Henry Brem John L Cameron Clarence C Lee Leslie A Fecher Gary L Gallia Peter Gibbs Dung Le Robert L Giuntoli Michael Goggins Michael D Hogarty Matthias Holdhoff Seung Mo Hong Yuchen Jiao Hartmut H Juhl Jenny J Kim Giulia Siravegna Daniel A Laheru Calogero Lauricella Michael Lim Evan J Lipson Suely Kazue Nagahashi Marie George J Netto Kelly S Oliner Alessandro Olivi Louise Olsson Gregory J Riggins Andrea Sartore Bianchi Kerstin Schmidt le Ming Shih Sueli Mieko Oba Shinjo Salvatore Siena Dan Theodorescu Jeanne Tie Timothy T Harkins Silvio Veronese Tian Li Wang Jon D Weingart Christopher L Wolfgang Laura D Wood Dongmei Xing Ralph H Hruban Jian Wu Peter J Allen C Max Schmidt Michael A Choti Victor E Velculescu Kenneth W Kinzler Bert Vogelstein Nickolas Papadopoulos Luis A Diaz Jr Science Translational Medicine 19 Feb 2014 224ra24 Circulating tumor DNA can be used in a variety of clinical and investigational settings across tumor types and stages for screening diagnosis and identifying mutations responsible for therapeutic response and drug resistance Citation Manager Formats BibTeX Bookends EasyBib EndNote tagged EndNote 8 xml Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Share Detection of Circulating Tumor DNA in Early and Late Stage Human

    Original URL path: http://stm.sciencemag.org/content/6/224/224ra24?ijkey=d770117e16f91f9915b8ad41e9c8a96471c9d5ae&keytype2=tf_ipsecsha (2016-02-10)
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  • Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti-EGFR Therapies in Colorectal Cancer | Science Translational Medicine
    this author on Google Scholar Find this author on PubMed Search for this author on this site Federica Di Nicolantonio Department of Oncology University of Torino 10060 Candiolo Torino Italy Institute for Cancer Research and Treatment 10060 Candiolo Torino Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Alberto Bardelli Department of Oncology University of Torino 10060 Candiolo Torino Italy Institute for Cancer Research and Treatment 10060 Candiolo Torino Italy Italian Foundation for Cancer Research Institute of Molecular Oncology 20139 Milano Italy Find this author on Google Scholar Find this author on PubMed Search for this author on this site Article Figures Data Info Metrics eLetters PDF You are currently viewing the abstract View Full Text Abstract Colorectal cancers CRCs that are sensitive to the anti epidermal growth factor receptor EGFR antibodies cetuximab or panitumumab almost always develop resistance within several months of initiating therapy We report the emergence of polyclonal KRAS NRAS and BRAF mutations in CRC cells with acquired resistance to EGFR blockade Regardless of the genetic alterations resistant cells consistently displayed mitogen activated protein kinase kinase MEK and extracellular signal regulated kinase ERK activation which persisted after EGFR blockade Inhibition of MEK1 2 alone failed to impair the growth of resistant cells in vitro and in vivo An RNA interference screen demonstrated that suppression of EGFR together with silencing of MEK1 2 was required to hamper the proliferation of resistant cells Indeed concomitant pharmacological blockade of MEK and EGFR induced prolonged ERK inhibition and severely impaired the growth of resistant tumor cells Heterogeneous and concomitant mutations in KRAS and NRAS were also detected in plasma samples from patients who developed resistance to anti EGFR antibodies A mouse xenotransplant from a CRC patient who responded and subsequently relapsed upon EGFR therapy showed exquisite sensitivity to combinatorial treatment with MEK and EGFR inhibitors Collectively these results identify genetically distinct mechanisms that mediate secondary resistance to anti EGFR therapies all of which reactivate ERK signaling These observations provide a rational strategy to overcome the multifaceted clonal heterogeneity that emerges when tumors are treated with targeted agents We propose that MEK inhibitors in combination with cetuximab or panitumumab should be tested in CRC patients who become refractory to anti EGFR therapies Copyright 2014 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol 6 Issue 224 19 February 2014 Table of Contents Article Tools Email Thank you for your interest in spreading the word about Science Translational Medicine NOTE We only request your email address so that the person you are recommending the page to knows that you wanted them to see it and that it is not junk mail We do not capture any email address Your Email Your Name Send To Enter multiple addresses on separate lines or separate them with commas You are going to email the following Blockade of EGFR and MEK Intercepts Heterogeneous Mechanisms of Acquired Resistance to Anti EGFR Therapies in

    Original URL path: http://stm.sciencemag.org/content/6/224/224ra26?ijkey=c83b6f003ef31e2a83e8743912fc944c9e780138&keytype2=tf_ipsecsha (2016-02-10)
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  • Activation of ERBB2 Signaling Causes Resistance to the EGFR-Directed Therapeutic Antibody Cetuximab | Science Translational Medicine
    activation of ERBB2 signaling in cell lines either through ERBB2 amplification or through heregulin up regulation leads to persistent extracellular signal regulated kinase 1 2 signaling and consequently to cetuximab resistance Inhibition of ERBB2 or disruption of ERBB2 ERBB3 heterodimerization restores cetuximab sensitivity in vitro and in vivo A subset of colorectal cancer patients who exhibit either de novo or acquired resistance to cetuximab based therapy has ERBB2 amplification or high levels of circulating heregulin Collectively these findings identify two distinct resistance mechanisms both of which promote aberrant ERBB2 signaling that mediate cetuximab resistance Moreover these results suggest that ERBB2 inhibitors in combination with cetuximab represent a rational therapeutic strategy that should be assessed in patients with cetuximab resistant cancers Footnotes These authors contributed equally to this work Citation K Yonesaka K Zejnullahu I Okamoto T Satoh F Cappuzzo J Souglakos D Ercan A Rogers M Roncalli M Takeda Y Fujisaka J Philips T Shimizu O Maenishi Y Cho J Sun A Destro K Taira K Takeda T Okabe J Swanson H Itoh M Takada E Lifshits K Okuno J A Engelman R A Shivdasani K Nishio M Fukuoka M Varella Garcia K Nakagawa P A Jänne Activation of ERBB2 Signaling Causes Resistance to the EGFR Directed Therapeutic Antibody Cetuximab Sci Transl Med 3 99ra86 2011 Copyright 2011 American Association for the Advancement of Science View Full Text Science Translational Medicine Vol 3 Issue 99 07 September 2011 Table of Contents Article Tools Email Thank you for your interest in spreading the word about Science Translational Medicine NOTE We only request your email address so that the person you are recommending the page to knows that you wanted them to see it and that it is not junk mail We do not capture any email address Your Email Your Name Send To Enter multiple addresses on separate lines or separate them with commas You are going to email the following Activation of ERBB2 Signaling Causes Resistance to the EGFR Directed Therapeutic Antibody Cetuximab Message Subject Your Name has forwarded a page to you from Science Translational Medicine Message Body Your Name thought you would like to see this page from the Science Translational Medicine web site Your Personal Message Send Message Download Powerpoint Print Save to my folders User Name Password Remember my user name password Submit Alerts Please log in to add an alert for this article Username Enter your Sciencemag org username Password Enter the password that accompanies your username Log in Request Permissions Citation tools Activation of ERBB2 Signaling Causes Resistance to the EGFR Directed Therapeutic Antibody Cetuximab By Kimio Yonesaka Kreshnik Zejnullahu Isamu Okamoto Taroh Satoh Federico Cappuzzo John Souglakos Dalia Ercan Andrew Rogers Massimo Roncalli Masayuki Takeda Yasuhito Fujisaka Juliet Philips Toshio Shimizu Osamu Maenishi Yonggon Cho Jason Sun Annarita Destro Koichi Taira Koji Takeda Takafumi Okabe Jeffrey Swanson Hiroyuki Itoh Minoru Takada Eugene Lifshits Kiyotaka Okuno Jeffrey A Engelman Ramesh A Shivdasani Kazuto Nishio Masahiro Fukuoka Marileila Varella Garcia Kazuhiko Nakagawa Pasi A Jänne

    Original URL path: http://stm.sciencemag.org/content/3/99/99ra86?ijkey=4a82ceaec7f97341bb09929da5363acb112071b9&keytype2=tf_ipsecsha (2016-02-10)
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  • Mechanisms of Acquired Crizotinib Resistance in ALK-Rearranged Lung Cancers | Science Translational Medicine
    Table of Contents Article Tools Email Thank you for your interest in spreading the word about Science Translational Medicine NOTE We only request your email address so that the person you are recommending the page to knows that you wanted them to see it and that it is not junk mail We do not capture any email address Your Email Your Name Send To Enter multiple addresses on separate lines or separate them with commas You are going to email the following Mechanisms of Acquired Crizotinib Resistance in ALK Rearranged Lung Cancers Message Subject Your Name has forwarded a page to you from Science Translational Medicine Message Body Your Name thought you would like to see this page from the Science Translational Medicine web site Your Personal Message Send Message Download Powerpoint Print Save to my folders User Name Password Remember my user name password Submit Alerts Please log in to add an alert for this article Username Enter your Sciencemag org username Password Enter the password that accompanies your username Log in Request Permissions Citation tools Mechanisms of Acquired Crizotinib Resistance in ALK Rearranged Lung Cancers By Ryohei Katayama Alice T Shaw Tahsin M Khan Mari Mino Kenudson Benjamin J Solomon Balazs Halmos Nicholas A Jessop John C Wain Alan Tien Yeo Cyril Benes Lisa Drew Jamal Carlos Saeh Katherine Crosby Lecia V Sequist A John Iafrate Jeffrey A Engelman Science Translational Medicine 08 Feb 2012 120ra17 Multiple mechanisms of crizotinib resistance were identified in lung cancer patients including new secondary ALK mutations and activation of receptor tyrosine kinases Citation Manager Formats BibTeX Bookends EasyBib EndNote tagged EndNote 8 xml Medlars Mendeley Papers RefWorks Tagged Ref Manager RIS Zotero Share Mechanisms of Acquired Crizotinib Resistance in ALK Rearranged Lung Cancers By Ryohei Katayama Alice T Shaw Tahsin M Khan Mari Mino Kenudson Benjamin J Solomon Balazs Halmos Nicholas A Jessop John C Wain Alan Tien Yeo Cyril Benes Lisa Drew Jamal Carlos Saeh Katherine Crosby Lecia V Sequist A John Iafrate Jeffrey A Engelman Science Translational Medicine 08 Feb 2012 120ra17 Multiple mechanisms of crizotinib resistance were identified in lung cancer patients including new secondary ALK mutations and activation of receptor tyrosine kinases Permalink Copy Related Content Perspective Escaping ALK Inhibition Mechanisms of and Strategies to Overcome Resistance Podcast Science Translational Medicine Podcast 8 February 2012 Research Article A Genomics Based Classification of Human Lung Tumors Research Article A combination therapy for KRAS driven lung adenocarcinomas using lipophilic bisphosphonates and rapamycin Similar Articles in PubMed Google Scholar Cited By MM 151 overcomes acquired resistance to cetuximab and panitumumab in colorectal cancers harboring EGFR extracellular domain mutations ALK inhibitors in non small cell lung cancer the latest evidence and developments Activation of EGFR Bypass Signaling by TGF alpha Overexpression Induces Acquired Resistance to Alectinib in ALK Translocated Lung Cancer Cells Emerging Options After Progression During Crizotinib Therapy Efficacy of a Cancer Vaccine against ALK Rearranged Lung Tumors Evolutionary Precision Medicine A Role for Repeat Epidermal Growth Factor Receptor Analysis in

    Original URL path: http://stm.sciencemag.org/content/4/120/120ra17?ijkey=33100841cf25a101169a00726a7f44fcb334ae87&keytype2=tf_ipsecsha (2016-02-10)
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