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      A Broad-Spectrum Integrative Design for Cancer Prevention and Therapy

      research-article
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      Seminars in cancer biology
      Multi-targeted, cancer hallmarks, phytochemicals, targeted therapy, integrative medicine

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          Abstract

          Targeted therapies and the consequent adoption of “personalized” oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity “broad-spectrum” therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested; many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to help us address disease relapse, which is a substantial and longstanding problem, so a proposed agenda for future research is offered.

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          Author and article information

          Journal
          9010218
          1211
          Semin Cancer Biol
          Semin. Cancer Biol.
          Seminars in cancer biology
          1044-579X
          1096-3650
          12 March 2016
          December 2015
          01 December 2016
          : 35
          : Suppl
          : S276-S304
          Affiliations
          [1 ]Block Center for Integrative Cancer Treatment, Skokie, Illinois, United States
          [2 ]Getting to Know Cancer, Truro, Nova Scotia, Canada
          [3 ]Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
          [4 ]Winship Cancer Institute of Emory University, Atlanta, Georgia, United States
          [5 ]Department of Biology, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
          [6 ]Department of Biology, University of Rome “Tor Vergata”, Rome, Italy
          [7 ]Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina, United States
          [8 ]Department of Biology, Temple University, Philadelphia, Pennyslvania, United States
          [9 ]Department of Chemistry, College of Science, United Arab Emirates University, Al Ain, United Arab Emirates
          [10 ]Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States
          [11 ]Department of Biomedical Sciences, Ohio University, Athens, Ohio, United States
          [12 ]School of Chemical and Bio Technology, SASTRA University, Thanjavur, Tamil Nadu, India
          [13 ]University of Glasgow, Glasgow, United Kingdom
          [14 ]Department of Pharmaceutical Sciences, Larkin Health Sciences Institute, Miami, Florida, United States
          [15 ]Department of Pediatrics, State University of New York, Downstate Medical Center, Brooklyn, New York, United States
          [16 ]Department of BioMedical Sciences, School of Medicine, Creighton University, Omaha, Nebraska, United States
          [17 ]Head and Neck Cancer Biology Laboratory, University of Michigan, Ann Arbor, Michigan, United States
          [18 ]Instituto de Biomedicina de Sevilla, Consejo Superior de Investigaciones Cientificas, Seville, Spain
          [19 ]Centro di Ingegneria Genetica e Biotecnologia Avanzate Naples, Italy
          [20 ]Department of Molecular Medicine and Medical Biotechnology, Federico II, Via Pansini 5, 80131, Naples, Italy
          [21 ]Stanford University Division of Oncology, Departments of Medicine and Patholog, Stanford, California, United States
          [22 ]Department of Pathology, Microbiology, and Immunology, University of South Carolina, School of Medicine, Columbia, South Carolina, United States
          [23 ]School of Biotechnology, Jawaharlal Nehru University, New Delhi, India
          [24 ]Department of Pediatrics, University of British Columbia, Michael Cuccione Childhood Cancer Research Program, Child and Family Research Institute, Vancouver, British Columbia, Canada
          [25 ]Ovarian and Prostate Cancer Research Laboratory, Guildford, Surrey, United Kingdom
          [26 ]Department of Biology, Alderson Broaddus University, Philippi, West Virginia, United States
          [27 ]Cancer Immunology Branch, Division of Cancer Biology, National Cancer Center, Goyang, Gyeonggi, Korea
          [28 ]Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, United Kingdom
          [29 ]Department of Nutrition, Faculty of Medicine, University of Oslo, Oslo, Norway
          [30 ]Cancer Biology Research Laboratory, Southern Connecticut State University, New Haven, Connecticut, United States
          [31 ]School of Medicine and Public Health, University of Wisconsin-Madison, Madison, Wisconsin, United States
          [32 ]Department of Oncology and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden
          [33 ]Department of Oncology, Istituto Di Ricovero e Cura a Carattere Scientifico - Istituto di Ricerche Farmacologiche Mario Negri, Milan, Italy
          [34 ]Department of Cellular and Molecular Biology, the University of Texas Health Science Center at Tyler, Tyler, Texas, United States
          [35 ]Section of Clinical Immunology, Allergy, and Rheumatology, Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States
          [36 ]Children‘s Medical Center Research Institute, University of Texas – Southwestern Medical Center, Dallas, Texas, United States
          [37 ]Department of Pathology & Immunology, Baylor College of Medicine, Houston, Texas, United States
          [38 ]Department of Surgery and Cancer Biology, Division of Surgical Oncology, Vanderbilt University School of Medicine, Nashville, Tennessee, United States
          [39 ]Department of Medicine, Duke University Medical Center, Durham, North Carolina, United States
          [40 ]Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan, United States
          [41 ]Rowett Institute of Nutrition and Health, University of Aberdeen, Aberdeen, Scotland, United Kingdom
          [42 ]College of Medicine & Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates
          [43 ]Department of Hematology and Medical Oncology, Emory University, Atlanta, Georgia, United States
          [44 ]Discipline of Nutrition, University of Auckland and Auckland Cancer Society Research Center Auckland, New Zealand
          [45 ]Dipartimento di Scienze per la Qualità della Vita Alma Mater Studiorum-Università di Bologna, Rimini, Italy
          [46 ]Department of Molecular & Cell Biology, University of California Berkeley, Berkeley, California, United States
          [47 ]Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge, United Kingdom
          [48 ]Department of Orthopedic Surgery, Nara Medical University, Kashihara, Nara, Japan
          [49 ]Medicine and Research Services, Veterans Affairs San Diego Healthcare System & University of California, San Diego, San Diego, California, United States
          [50 ]Molecular Therapy and Pharmacogenomics Unit, Azienda Ospedaliera Istituti Ospitalieri di Cremona, Cremona, Italy
          [51 ]Physics Department, School of Applied Mathematics and Physical Sciences, National Technical University of Athens, Athens, Greece
          [52 ]First Department of Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Lübeck, Germany
          [53 ]Getting to Know Cancer, Guelph, Canada
          [54 ]Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina, United States
          [55 ]Departments of Environmental Science, Microbiology and Immunology, Dalhousie University, Halifax, Nova Scotia, Canada
          [56 ]Department of Pathology, New York Medical College, Valhalla, New York, United States
          [57 ]University of Illinois at Urbana Champaign, Champaign, Illinois, United States
          [58 ]Charles University in Prague, Third Faculty of Medicine, Prague, Czech Republic
          [59 ]School of Medical Laboratory and Radiation Sciences, Old Dominion University, Norfolk Virginia, United States
          [60 ]College of Pharmacy, University of South Carolina, Columbia, South Carolina, United States
          [61 ]Tisch Cancer Institute, Mount Sinai School of Medicine, New York New York, United States
          [62 ]Department of Life Sciences, Tzu-Chi University, Hualien, Taiwan
          [63 ]Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, United States
          [64 ]Department of Medical and Health Sciences, Linköping University, Linköping, Sweden
          [65 ]Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
          [66 ]Cardiff University School of Medicine, Heath Park, Cardiff, United Kingdom
          [67 ]Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States
          [68 ]Harvard Medical School, Harvard University, Cambridge, Massachusetts, United States
          [69 ]Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States
          [70 ]Henry Ford Hospital, Detroit, Michigan, United States
          [71 ]Inflammation and Cancer Research, National Cancer Institute (Retired), National Institutes of Health, Bethesda, Maryland, United States
          [72 ]University of Maryland BioPark, Innovation Center, KoDiscovery, Baltimore, Maryland, United States
          [73 ]Moffitt Cancer Center, University of South Florida College of Medicine, Tampa, Florida, United States
          [74 ]Department of Surgery, St. Luke’s Roosevelt Hospital, New York New York, United States
          [75 ]Department of Medicine, Tulane University Health Sciences Center, New Orleans, Louisiana, United States
          [76 ]The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
          [77 ]New Jersey Medical School, Rutgers University, Newark, New Jersey, United States
          [78 ]College of Pharmacy, Seoul National University, South Korea
          [79 ]Department of Neurosurgery, Rush University Medical Center, Chicago, Illinois, United States
          [80 ]Department of Microbiology and Immunology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
          [81 ]Division of Nutritional Sciences, Cornell University, Ithaca, New York, United States
          [82 ]Georgia Regents University, Augusta, Georgia, United States
          [83 ]Andrus Gerontology Center, Division of Biogerontology, University of Southern California, Los Angeles, California, United States
          [84 ]Department of Molecular and Integrative Physiology and Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan, United States
          [85 ]Children's Cancer Institute Australia, Kensington New South Wales, Australia
          [86 ]Department of Biomedical Engineering, McGill University, Montréal, Canada
          [87 ]Department of Science, University Roma Tre, Rome, Italy
          [88 ]Metabolomic Unit, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Technology Park of Bizkaia, Bizkaia, Spain
          [89 ]Biodonostia Institute, Gipuzkoa, Spain
          [90 ]Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
          [91 ]Field of Genetics, Genomics, and Development, Department of Molecular Biology and Genetics, Cornell University, Ithaca, New York, United States
          [92 ]Department of Experimental Therapeutics, University of Texas MD Anderson Cancer Center, Houston, Texas, United States
          [93 ]Department of Comparative Pathobiology, Purdue University Center for Cancer Research, West Lafayette, Indiana, United States
          [94 ]Mor-NuCo, Inc, Purdue Research Park, West Lafayette, Indiana, United States
          [95 ]Harvard-MIT Division of Health Sciences and Technology, Harvard Medical School, Boston, Massachusetts, United States
          [96 ]Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States
          [97 ]MRC Mitochondrial Biology Unit, Wellcome Trust-MRC Building, Hills Road, Cambridge, United Kingdom
          [98 ]University of Florence, Florence, Italy
          [99 ]Medical Scientist Training Program, Mayo Graduate School, Mayo Medical School, Mayo Clinic, Rochester, Minnesota, United States
          [100 ]Laboratory of Inflammatory Mediators, State University of West Paraná, UNIOESTE, Paraná, Brazil
          [101 ]Medical Oncology Department, University Campus Bio-Medico, Rome, Italy
          [102 ]Center for Medical Research, University of Tübingen, Tübingen, Germany
          [103 ]Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States
          [104 ]Department of Otolaryngology-Head and Neck, Medical School, University of Michigan, Ann Arbor, Michigan, United States
          [105 ]Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy
          [106 ]Center for Clinical and Experimental Photodermatology, Clinic for Dermatology, Venerology and Allergology, The Saarland University Hospital, Homburg, Germany
          [107 ]Department of Biology, University of Rochester, Rochester, New York, United States
          [108 ]Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy &.National Cancer Institute Giovanni Paolo II, Bari, Italy
          [109 ]Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
          [110 ]White River Junction Veterans Affairs Medical Center, White River Junction, Vermont, United States
          [111 ]Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States
          [112 ]Centre de Rechercher du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, Montréal, Quebec, Canada
          [113 ]Université de Montréal, Département de Radiologie, Radio-Oncologie et Médicine Nucléaire, Montréal, Quebec, Canada
          [114 ]Department of Environmental Sciences, Faculty of Agriculture and Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
          [115 ]Institute of Food Sciences National Research Council, Avellino, Italy
          [116 ]Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado, United States
          [117 ]Sanus Biosciences, San Diego, California, United States
          [118 ]Experimental Therapeutics and Translational Oncology Program, Instituto de Biología Molecular y Celular del Cáncer, CSIC-Universidad de Salamanca, Salamanca, Spain
          [119 ]Department of Biology, University of Miami, Miami, Florida, United States
          [120 ]Department of Immunology, Kurume University School of Medicine, Kurume, Fukuoka, Japan
          [121 ]Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States
          [122 ]Department of Pathology, Louisiana State University, Health Shreveport, Shreveport, Louisiana, United States
          [123 ]Department of Oncology, Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States
          [124 ]Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, United State
          [125 ]Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York, United States
          [126 ]National Research Council, Institute of Translational Pharmacology, Rome, Italy
          [127 ]Advanced Molecular Science Research Centre (Centre for Advanced Research), King George's Medical University, Lucknow, Uttar Pradesh, India
          [128 ]Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States
          [129 ]DSTest Laboratories, Purdue Research Park, Indianapolis, Indiana, United States
          [130 ]Department of Biomedical Science, Sheffield Cancer Research Centre, University of Sheffield, Sheffield, United Kingdom
          [131 ]Huntsman Cancer Institute and Department of Internal Medicine, University of Utah, Salt Lake City, Utah, United States
          [132 ]Centre de Recherche du Centre Hospitalier de l’Université de Montréal, Faculté de Pharmacie et Institut du Cancer de Montréal, Montréal, Quebec, Canada
          [133 ]Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, United States
          [134 ]Department of Molecular Diagnostics, Sentara Healthcare, Norfolk, Virginia, United States
          [135 ]Department of Clinical Pharmacy and Therapeutics, Applied Science University, Amman, Jordan
          [136 ]Department of Surgery, Royal Adelaide Hospital, Adelaide, Australia
          [137 ]Departments of Radiation Oncology & Molecular Radiation Sciences, Oncology and Urology, Johns Hopkins School of Medicine, Baltimore, Maryland, United States
          [138 ]Department of Surgery, University of Toronto, Division of Urology, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
          [139 ]Department of Internal Medicine, New York University Lutheran Medical Center, Brooklyn, New York, New York, United States
          [140 ]Department of Urology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States
          [141 ]Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, United States
          [142 ]The School of Life Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang, China
          [143 ]Life Sciences Division, Lawrence Berkeley National Lab, Berkeley, California, United States
          [144 ]Department of Biology, Jackson State University, Jackson, Mississippi, United States
          [145 ]Washington State University College of Pharmacy, Spokane, Washington, United States
          [146 ]Atlanta Veterans Administration Medical Center, Atlanta, Georgia, United States
          [147 ]Department of Dermatology, Emory University School of Medicine, Emory University, Atlanta, Georgia, United States
          [148 ]Lancaster Environment Centre, Lancaster University, Bailrigg, Lancaster, United Kingdom
          Author notes
          [* ]Corresponding author at: Keith I. Block, MD, Block Center for Integrative Cancer Treatment, 5230 Old Orchard Road, Skokie IL 60077, Telephone: 847-492-3040, Fax: 847-493-3045, drblock@ 123456blockmedical.com
          []Corresponding author at: Leroy Lowe, Getting to Know Cancer, Room 229A, 36 Arthur Street, Truro, Nova Scotia, Canada, Telephone: 902-893-5362, Fax: 902-893-5610, Leroy.lowe@ 123456gettingtoknowcancer.org
          Article
          PMC4819002 PMC4819002 4819002 nihpa754223
          10.1016/j.semcancer.2015.09.007
          4819002
          26590477
          e155806d-588f-412c-92f7-fa2c8310c927
          History
          Categories
          Article

          Multi-targeted,cancer hallmarks,phytochemicals,targeted therapy,integrative medicine

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