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 be relatively inexpensive, it should help us address stages and types of cancer that lack conventional treatment, and it may reduce relapse risks. A proposed agenda for future research is offered.

1st Department of Medicine University Hospital Schleswig Holstein Campus Lübeck Lübeck Germany

Advanced Molecular Science Research Centre King George's Medical University Lucknow Uttar Pradesh India

Albert Einstein College of Medicine and Montefiore Medical Center Bronx NY United States

Andrus Gerontology Center Division of Biogerontology University of Southern California Los Angeles CA United States

Biodonostia Institute Gipuzkoa Spain

Block Center for Integrative Cancer Treatment Skokie IL United States

Cancer Biology Research Laboratory Southern Connecticut State University New Haven CT United States

Cancer Immunology Branch Division of Cancer Biology National Cancer Center Goyang Gyeonggi Republic of Korea

Cancer Immunology Branch Division of Cancer Biology National Cancer Center Goyang Gyeonggi Republic of Korea; Department of Medicine Tulane University Health Sciences Center New Orleans LA United States

Cardiff University School of Medicine Heath Park Cardiff United Kingdom

Center for Clinical and Experimental Photodermatology Clinic for Dermatology Venerology and Allergology The Saarland University Hospital Homburg Germany

Center for Medical Research University of Tübingen Tübingen Germany

Centre de Recherche du Centre Hospitalier de l'Université de Montréal Faculté de Pharmacie et Institut du Cancer de Montréal Montréal Quebec Canada

Centre de Rechercher du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal Montréal Quebec Canada; Université de Montréal Département de Radiologie Radio Oncologie et Médicine Nucléaire Montréal Quebec Canada

Centro di Ingegneria Genetica e Biotecnologia Avanzate Naples Italy; Department of Molecular Medicine and Medical Biotechnology Federico 2 Via Pansini 5 80131 Naples Italy

Charles University Prague 3rd Faculty of Medicine Prague Czech Republic

Children's Cancer Institute Australia Kensington New South Wales Australia

Children's Medical Center Research Institute University of Texas Southwestern Medical Center Dallas TX United States

College of Medicine and Health Sciences United Arab Emirates University Al Ain United Arab Emirates

College of Pharmacy Seoul National University South Korea

College of Pharmacy University of South Carolina Columbia SC United States

Department of Basic Medical Sciences Neurosciences and Sensory Organs University of Bari Medical School Bari Italy and National Cancer Institute Giovanni Paolo 2 Bari Italy

Department of Biology Alderson Broaddus University Philippi WV United States

Department of Biology College of Science United Arab Emirates University Al Ain United Arab Emirates

Department of Biology Jackson State University Jackson MS United States

Department of Biology Temple University Philadelphia PA United States

Department of Biology University of Miami Miami FL United States

Department of Biology University of Rochester Rochester NY United States

Department of Biology University of Rome Tor Vergata Rome Italy

Department of Biomedical Engineering McGill University Montréal Canada

Department of Biomedical Science Sheffield Cancer Research Centre University of Sheffield Sheffield United Kingdom

Department of Biomedical Sciences Ohio University Athens OH United States

Department of BioMedical Sciences School of Medicine Creighton University Omaha NE United States

Department of Cancer Biology Perelman School of Medicine University of Pennsylvania Philadelphia PA United States

Department of Cellular and Molecular Biology the University of Texas Health Science Center at Tyler Tyler TX United States

Department of Chemistry College of Science United Arab Emirates University Al Ain United Arab Emirates

Department of Clinical Pharmacy and Therapeutics Applied Science University Amman Jordan

Department of Comparative Pathobiology Purdue University Center for Cancer Research West Lafayette IN United States

Department of Environmental and Radiological Health Sciences Colorado State University Fort Collins CO United States

Department of Environmental Sciences Faculty of Agriculture and Department of Pathology Faculty of Medicine Dalhousie University Halifax Nova Scotia Canada

Department of Experimental and Clinical Medicine University of Florence Florence Italy

Department of Experimental Therapeutics University of Texas MD Anderson Cancer Center Houston TX United States

Department of Hematology and Medical Oncology Emory University Atlanta GA United States

Department of Immunology Kurume University School of Medicine Kurume Fukuoka Japan

Department of Internal Medicine New York University Lutheran Medical Center Brooklyn New York NY United States

Department of Life Sciences Tzu Chi University Hualien Taiwan

Department of Medical and Health Sciences Linköping University Linköping Sweden; Department of Microbiology Tumor and Cell Biology Karolinska Institutet Stockholm Sweden

Department of Medical and Surgical Sciences University of Bologna Bologna Italy

Department of Medical Surgery and Health Sciences University of Trieste Trieste Italy; Molecular Therapy and Pharmacogenomics Unit Azienda Ospedaliera Istituti Ospitalieri di Cremona Cremona Italy

Department of Medicine Duke University Medical Center Durham NC United States

Department of Medicine Duke University Medical Center Durham NC United States; Duke Molecular Physiology Institute Duke University Medical Center Durham NC United States

Department of Medicine Georgia Regents University Cancer Center Augusta GA United States

Department of Medicine Memorial Sloan Kettering Cancer Center New York NY United States

Department of Medicine University of Maryland School of Medicine Baltimore MD United States

Department of Medicine University of Miami Miller School of Medicine Miami FL United States

Department of Microbiology and Immunology School of Medicine College of Medicine Taipei Medical University Taipei Taiwan

Department of Molecular and Cell Biology University of California Berkeley Berkeley CA United States

Department of Molecular and Integrative Physiology and Department of Internal Medicine Division of Gastroenterology University of Michigan Ann Arbor MI United States

Department of Molecular Diagnostics Sentara Healthcare Norfolk VA United States

Department of Neurosurgery Rush University Medical Center Chicago IL United States

Department of Nutrition Faculty of Medicine University of Oslo Oslo Norway

Department of Oncology and Department of Clinical and Experimental Medicine Linköping University Linköping Sweden

Department of Oncology Istituto Di Ricovero e Cura a Carattere Scientifico Istituto di Ricerche Farmacologiche Mario Negri Milan Italy

Department of Oncology Johns Hopkins University School of Medicine and the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore MD United States

Department of Oncology Karmanos Cancer Institute Wayne State University Detroit MI United States

Department of Orthopedic Surgery Nara Medical University Kashihara Nara Japan

Department of Otolaryngology Head and Neck Medical School University of Michigan Ann Arbor MI United States

Department of Otolaryngology Head and Neck Surgery Johns Hopkins University School of Medicine Baltimore MD United States

Department of Pathology and Cell Biology Columbia University Medical Center New York NY United States

Department of Pathology and Immunology Baylor College of Medicine Houston TX United States

Department of Pathology Johns Hopkins University School of Medicine Baltimore MD United States

Department of Pathology Louisiana State University Health Shreveport Shreveport LA United States

Department of Pathology Microbiology and Immunology University of South Carolina School of Medicine Columbia SC United States

Department of Pathology New York Medical College Valhalla NY United States

Department of Pediatrics State University of New York Downstate Medical Center Brooklyn NY United States

Department of Pediatrics University of British Columbia Michael Cuccione Childhood Cancer Research Program Child and Family Research Institute Vancouver British Columbia Canada

Department of Pharmaceutical Sciences College of Pharmacy Larkin Health Sciences Institute Miami FL United States

Department of Radiation Oncology University of Alabama at Birmingham School of Medicine Birmingham AL United States

Department of Science University Roma Tre Rome Italy

Department of Surgery and Cancer Biology Division of Surgical Oncology Vanderbilt University School of Medicine Nashville TN United States

Department of Surgery Royal Adelaide Hospital Adelaide Australia

Department of Surgery St Luke's Roosevelt Hospital New York NY United States

Department of Surgery University of Toronto Division of Urology Sunnybrook Health Sciences Centre Toronto Ontario Canada

Department of Urology Massachusetts General Hospital Harvard Medical School Boston MA United States

Departments of Biological Chemistry and Oncology Member at Large Sidney Kimmel Comprehensive Cancer Center Johns Hopkins University School of Medicine Baltimore MD United States

Departments of Environmental Science Microbiology and Immunology Dalhousie University Halifax Nova Scotia Canada

Departments of Radiation Oncology and Molecular Radiation Sciences Oncology and Urology Johns Hopkins School of Medicine Baltimore MD United States

Dipartimento di Scienze per la Qualità della Vita Alma Mater Studiorum Università di Bologna Rimini Italy

Discipline of Nutrition and Auckland Cancer Society Research Centre University of Auckland Auckland New Zealand

Division of Nutritional Sciences Cornell University Ithaca NY United States

DSTest Laboratories Purdue Research Park Indianapolis IN United States

Duke Molecular Physiology Institute Duke University Medical Center Durham NC United States

Experimental Therapeutics and Translational Oncology Program Instituto de Biología Molecular y Celular del Cáncer CSIC Universidad de Salamanca Salamanca Spain

Faculty of Health and Medical Sciences University of Surrey Guildford Surrey United Kingdom

Field of Genetics Genomics and Development Department of Molecular Biology and Genetics Cornell University Ithaca NY United States

Getting to Know Cancer Guelph Canada

Getting to Know Cancer Truro Nova Scotia Canada; Lancaster Environment Centre Lancaster University Bailrigg Lancaster United Kingdom

Harvard MIT Division of Health Sciences and Technology Harvard Medical School Boston MA United States; Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge MA United States

Head and Neck Cancer Biology Laboratory University of Michigan Ann Arbor MI United States

Henry Ford Hospital Detroit MI United States

Huntsman Cancer Institute and Department of Internal Medicine University of Utah Salt Lake City UT United States

Inflammation and Cancer Research National Cancer Institute National Institutes of Health Bethesda MD United States

Institute of Food Sciences National Research Council Avellino Italy

Instituto de Biomedicina de Sevilla Consejo Superior de Investigaciones Cientificas Seville Spain

Koch Institute for Integrative Cancer Research Massachusetts Institute of Technology Cambridge MA United States

Laboratory Medicine and Pathology Mayo Clinic Rochester MN United States

Laboratory of Inflammatory Mediators State University of West Paraná UNIOESTE Paraná Brazil

Laboratory of Oncology Istituto Giannina Gaslini Genoa Italy

Life Sciences Division Lawrence Berkeley National Lab Berkeley CA United States

Lineberger Comprehensive Cancer Center University of North Carolina Chapel Hill NC United States

Medical Oncology Department University Campus Bio Medico Rome Italy

Medical Research Council Cancer Unit University of Cambridge Hutchison MRC Research Centre Cambridge United Kingdom

Medical Scientist Training Program Mayo Graduate School Mayo Medical School Mayo Clinic Rochester MN United States

Medicine and Research Services Veterans Affairs San Diego Healthcare System and University of California San Diego CA United States

Metabolomic Unit Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas Technology Park of Bizkaia Bizkaia Spain

Moffitt Cancer Center University of South Florida College of Medicine Tampa FL United States

Mor NuCo Inc Purdue Research Park West Lafayette IN United States

MRC Mitochondrial Biology Unit Wellcome Trust MRC Building Hills Road Cambridge United Kingdom

National Research Council Institute of Translational Pharmacology Rome Italy

New Jersey Medical School Rutgers University Newark NJ United States

Ovarian and Prostate Cancer Research Laboratory Guildford Surrey United Kingdom

Physics Department School of Applied Mathematics and Physical Sciences National Technical University of Athens Athens Greece

Rowett Institute of Nutrition and Health University of Aberdeen Aberdeen Scotland United Kingdom

Sanus Biosciences San Diego CA United States

School of Biotechnology Jawaharlal Nehru University New Delhi India

School of Chemical and Bio Technology SASTRA University Thanjavur Tamil Nadu India

School of Medical Laboratory and Radiation Sciences Old Dominion University Norfolk VA United States

School of Medicine and Public Health University of Wisconsin Madison Madison WI United States

Section of Clinical Immunology Allergy and Rheumatology Department of Medicine Tulane University Health Sciences Center New Orleans LA United States

Stanford University Division of Oncology Department of Medicine and Pathology Stanford CA United States

The School of Life Science and Technology Harbin Institute of Technology Harbin Heilongjiang China

The Sol Goldman Pancreatic Cancer Research Center Department of Pathology Johns Hopkins University School of Medicine Baltimore MD United States

Tisch Cancer Institute Mount Sinai School of Medicine New York NY United States

University of Florence Florence Italy

University of Glasgow Glasgow United Kingdom

University of Illinois at Urbana Champaign Champaign IL United States

University of Maryland BioPark Innovation Center KoDiscovery Baltimore MD United States

University of Windsor Windsor Ontario Canada

Washington State University College of Pharmacy Spokane WA United States

White River Junction Veterans Affairs Medical Center White River Junction VT United States; Geisel School of Medicine at Dartmouth Hanover NH United States

Winship Cancer Institute of Emory University Atlanta GA United States

Winship Cancer Institute of Emory University Atlanta GA United States; Atlanta Veterans Administration Medical Center Atlanta GA United States; Department of Dermatology Emory University School of Medicine Emory University Atlanta GA United States

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The role of AMPK/mTOR signaling pathway in anticancer activity of metformin

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