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  • 1
    Publication Date: 2010-11-26
    Description: Non-small cell lung carcinoma (NSCLC) is the leading cause of cancer-related death worldwide, with an overall 5-year survival rate of only 10-15%. Deregulation of the Ras pathway is a frequent hallmark of NSCLC, often through mutations that directly activate Kras. p53 is also frequently inactivated in NSCLC and, because oncogenic Ras can be a potent trigger of p53 (ref. 3), it seems likely that oncogenic Ras signalling has a major and persistent role in driving the selection against p53. Hence, pharmacological restoration of p53 is an appealing therapeutic strategy for treating this disease. Here we model the probable therapeutic impact of p53 restoration in a spontaneously evolving mouse model of NSCLC initiated by sporadic oncogenic activation of endogenous Kras. Surprisingly, p53 restoration failed to induce significant regression of established tumours, although it did result in a significant decrease in the relative proportion of high-grade tumours. This is due to selective activation of p53 only in the more aggressive tumour cells within each tumour. Such selective activation of p53 correlates with marked upregulation in Ras signal intensity and induction of the oncogenic signalling sensor p19(ARF)( )(ref. 6). Our data indicate that p53-mediated tumour suppression is triggered only when oncogenic Ras signal flux exceeds a critical threshold. Importantly, the failure of low-level oncogenic Kras to engage p53 reveals inherent limits in the capacity of p53 to restrain early tumour evolution and in the efficacy of therapeutic p53 restoration to eradicate cancers.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011233/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011233/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Junttila, Melissa R -- Karnezis, Anthony N -- Garcia, Daniel -- Madriles, Francesc -- Kortlever, Roderik M -- Rostker, Fanya -- Brown Swigart, Lamorna -- Pham, David M -- Seo, Youngho -- Evan, Gerard I -- Martins, Carla P -- CA100193/CA/NCI NIH HHS/ -- CA98018/CA/NCI NIH HHS/ -- R01 CA100193/CA/NCI NIH HHS/ -- R01 CA100193-09/CA/NCI NIH HHS/ -- England -- Nature. 2010 Nov 25;468(7323):567-71. doi: 10.1038/nature09526.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of California San Francisco, Department of Pathology and Helen Diller Family Comprehensive Cancer Center, San Francisco, California 94143-0502, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21107427" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Carcinoma, Non-Small-Cell Lung/metabolism/*physiopathology ; Cell Proliferation ; Disease Models, Animal ; *Gene Expression Regulation, Neoplastic ; Lung Neoplasms/metabolism/*physiopathology ; Mice ; Proto-Oncogene Proteins p21(ras)/metabolism ; Tumor Suppressor Protein p53/genetics/*metabolism ; ras Proteins/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2015-07-15
    Description: We have sequenced the genomes of 110 small cell lung cancers (SCLC), one of the deadliest human cancers. In nearly all the tumours analysed we found bi-allelic inactivation of TP53 and RB1, sometimes by complex genomic rearrangements. Two tumours with wild-type RB1 had evidence of chromothripsis leading to overexpression of cyclin D1 (encoded by the CCND1 gene), revealing an alternative mechanism of Rb1 deregulation. Thus, loss of the tumour suppressors TP53 and RB1 is obligatory in SCLC. We discovered somatic genomic rearrangements of TP73 that create an oncogenic version of this gene, TP73Deltaex2/3. In rare cases, SCLC tumours exhibited kinase gene mutations, providing a possible therapeutic opportunity for individual patients. Finally, we observed inactivating mutations in NOTCH family genes in 25% of human SCLC. Accordingly, activation of Notch signalling in a pre-clinical SCLC mouse model strikingly reduced the number of tumours and extended the survival of the mutant mice. Furthermore, neuroendocrine gene expression was abrogated by Notch activity in SCLC cells. This first comprehensive study of somatic genome alterations in SCLC uncovers several key biological processes and identifies candidate therapeutic targets in this highly lethal form of cancer.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉George, Julie -- Lim, Jing Shan -- Jang, Se Jin -- Cun, Yupeng -- Ozretic, Luka -- Kong, Gu -- Leenders, Frauke -- Lu, Xin -- Fernandez-Cuesta, Lynnette -- Bosco, Graziella -- Muller, Christian -- Dahmen, Ilona -- Jahchan, Nadine S -- Park, Kwon-Sik -- Yang, Dian -- Karnezis, Anthony N -- Vaka, Dedeepya -- Torres, Angela -- Wang, Maia Segura -- Korbel, Jan O -- Menon, Roopika -- Chun, Sung-Min -- Kim, Deokhoon -- Wilkerson, Matt -- Hayes, Neil -- Engelmann, David -- Putzer, Brigitte -- Bos, Marc -- Michels, Sebastian -- Vlasic, Ignacija -- Seidel, Danila -- Pinther, Berit -- Schaub, Philipp -- Becker, Christian -- Altmuller, Janine -- Yokota, Jun -- Kohno, Takashi -- Iwakawa, Reika -- Tsuta, Koji -- Noguchi, Masayuki -- Muley, Thomas -- Hoffmann, Hans -- Schnabel, Philipp A -- Petersen, Iver -- Chen, Yuan -- Soltermann, Alex -- Tischler, Verena -- Choi, Chang-min -- Kim, Yong-Hee -- Massion, Pierre P -- Zou, Yong -- Jovanovic, Dragana -- Kontic, Milica -- Wright, Gavin M -- Russell, Prudence A -- Solomon, Benjamin -- Koch, Ina -- Lindner, Michael -- Muscarella, Lucia A -- la Torre, Annamaria -- Field, John K -- Jakopovic, Marko -- Knezevic, Jelena -- Castanos-Velez, Esmeralda -- Roz, Luca -- Pastorino, Ugo -- Brustugun, Odd-Terje -- Lund-Iversen, Marius -- Thunnissen, Erik -- Kohler, Jens -- Schuler, Martin -- Botling, Johan -- Sandelin, Martin -- Sanchez-Cespedes, Montserrat -- Salvesen, Helga B -- Achter, Viktor -- Lang, Ulrich -- Bogus, Magdalena -- Schneider, Peter M -- Zander, Thomas -- Ansen, Sascha -- Hallek, Michael -- Wolf, Jurgen -- Vingron, Martin -- Yatabe, Yasushi -- Travis, William D -- Nurnberg, Peter -- Reinhardt, Christian -- Perner, Sven -- Heukamp, Lukas -- Buttner, Reinhard -- Haas, Stefan A -- Brambilla, Elisabeth -- Peifer, Martin -- Sage, Julien -- Thomas, Roman K -- 5R01CA114102-08/CA/NCI NIH HHS/ -- England -- Nature. 2015 Aug 6;524(7563):47-53. doi: 10.1038/nature14664. Epub 2015 Jul 13.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. ; Departments of Pediatrics and Genetics, Stanford University, Stanford, California 94305, USA. ; Department of Pathology and Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany. ; Department of Pathology, College of Medicine, Hanyang University. 222 Wangsimniro, Seongdong-gu, Seoul 133-791, Korea. ; Vancouver General Hospital, Terry Fox laboratory, Vancouver, British Columbia V5Z 1L3, Canada. ; European Molecular Biology Laboratory, Genome Biology Unit, 69117 Heidelberg, Germany. ; Institute of Pathology, Center of Integrated Oncology Cologne-Bonn, University Hospital of Bonn, 53127 Bonn, Germany. ; Center for Cancer Genome Discovery, University of Ulsan College of Medicine, Asan Medical Center 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Department of Genetics, Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA. ; UNC Lineberger Comprehensive Cancer Center School of Medicine, University of North Carolina at Chapel Hill, North Carolina 27599-7295, USA. ; Institute of Experimental Gene Therapy and Cancer Research, Rostock University Medical Center, 18057 Rostock, Germany. ; Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany. ; Department of Internal Medicine, University Hospital of Cologne, 50931 Cologne, Germany. ; Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. ; 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Institute of Human Genetics, University Hospital Cologne, 50931 Cologne, Germany. ; 1] Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan. [2] Genomics and Epigenomics of Cancer Prediction Program, Institute of Predictive and Personalized Medicine of Cancer (IMPPC), Barcelona 08916, Spain. ; Division of Genome Biology, National Cancer Center Research Institute, Chuo-ku, Tokyo 1040045, Japan. ; Department of Pathology and Clinical Laboratories, National Cancer Center Hospital Chuo-ku, Tokyo 1040045, Japan. ; Department of Pathology, Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan. ; 1] Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany. ; Thoraxklinik at University Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg, Germany. ; 1] Translational Lung Research Center Heidelberg (TLRC-H), Member of German Center for Lung Research (DZL), Amalienstrasse 5, 69126 Heidelberg, Germany. [2] Institute of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, 69120 Heidelberg, Germany. ; Institute of Pathology, Jena University Hospital, Friedrich-Schiller-University, 07743 Jena, Germany. ; Institute of Surgical Pathology, University Hospital Zurich, 8091 Zurich, Switzerland. ; Department of Oncology, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Department of Thoracic and Cardiovascular Surgery, University of Ulsan College of Medicine, Asan Medical Center, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea. ; Thoracic Program, Vanderbilt-Ingram Cancer Center PRB 640, 2220 Pierce Avenue, Nashville, Tennessee 37232, USA. ; University Hospital of Pulmonology, Clinical Center of Serbia, Medical School, University of Belgrade, 11000 Belgrade, Serbia. ; Department of Surgery, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia. ; Department of Pathology, St. Vincent's Hospital, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia. ; Department of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, 3065 Melbourne, Victoria, Australia. ; Asklepios Biobank fur Lungenerkrankungen, Comprehensive Pneumology Center Munich, Member of the German Center for Lung Research (DZL), Asklepios Fachkliniken Munchen-Gauting 82131, Germany. ; Laboratory of Oncology, IRCCS Casa Sollievo della Sofferenza, Viale Cappuccini, 71013 San Giovanni, Rotondo, Italy. ; Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool Cancer Research Centre, 200 London Road, L69 3GA Liverpool, UK. ; University of Zagreb, School of Medicine, Department for Respiratory Diseases Jordanovac, University Hospital Center Zagreb, 10000 Zagreb, Croatia. ; Laboratory for Translational Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia. ; Charite Comprehensive Cancer Center, Charite Campus Mitte, 10115 Berlin, Germany. ; Tumor Genomics Unit, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS - Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan, Italy. ; Thoracic Surgery Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale Tumori, 20133 Milan, Italy. ; 1] Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, N-0424 Oslo, Norway. [2] Department of Oncology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway. ; Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0310 Oslo, Norway. ; Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. ; 1] West German Cancer Center, Department of Medical Oncology, University Hospital Essen, 45147 Essen, Germany. [2] German Cancer Consortium (DKTK), 69120 Heidelberg, Germany. ; Departments of Immunology, Genetics and Pathology, and Medical Sciences, Respiratory, Allergy and Sleep Research, Uppsala University, 75185 Uppsala, Sweden. ; Genes and Cancer Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), 08908 Hospitalet de Llobregat, Barcelona, Spain. ; 1] Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, N-5058 Bergen, Norway. [2] Department of Gynecology and Obstetrics, Haukeland University Hospital, N-5058 Bergen, Norway. ; Computing Center, University of Cologne, 50931 Cologne, Germany. ; 1] Computing Center, University of Cologne, 50931 Cologne, Germany. [2] Department of Informatics, University of Cologne, 50931 Cologne, Germany. ; Institute of Legal Medicine, University of Cologne, 50823 Cologne, Germany. ; Gastrointestinal Cancer Group Cologne, Center of Integrated Oncology Cologne-Bonn, Department I for Internal Medicine, University Hospital of Cologne, 50937 Cologne, Germany. ; 1] Department I of Internal Medicine, Center of Integrated Oncology Cologne-Bonn, University Hospital Cologne, 50937 Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. ; Computational Molecular Biology Group, Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. ; Department of Pathology and Molecular Diagnostics, Aichi Cancer Center, 464-8681 Nagoya, Japan. ; Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York 10065, USA. ; 1] Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany. [2] Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany. [3] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. ; Department of Pathology, CHU Grenoble INSERM U823, University Joseph Fourier, Institute Albert Bonniot 38043, CS10217 Grenoble, France. ; 1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany. ; 1] Department of Translational Genomics, Center of Integrated Oncology Cologne-Bonn, Medical Faculty, University of Cologne, 50931 Cologne, Germany. [2] Department of Pathology, University Hospital Cologne, 50937 Cologne, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/26168399" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 3
    Publication Date: 2008-08-22
    Description: Myc is a pleiotropic basic helix-loop-helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485609/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485609/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Soucek, Laura -- Whitfield, Jonathan -- Martins, Carla P -- Finch, Andrew J -- Murphy, Daniel J -- Sodir, Nicole M -- Karnezis, Anthony N -- Swigart, Lamorna Brown -- Nasi, Sergio -- Evan, Gerard I -- 2R01 CA98018/CA/NCI NIH HHS/ -- R01 CA098018/CA/NCI NIH HHS/ -- R01 CA098018-05/CA/NCI NIH HHS/ -- R01 CA098018-06/CA/NCI NIH HHS/ -- R01 CA098018-07/CA/NCI NIH HHS/ -- T32 CA108462/CA/NCI NIH HHS/ -- T32 CA108462-01/CA/NCI NIH HHS/ -- England -- Nature. 2008 Oct 2;455(7213):679-83. doi: 10.1038/nature07260. Epub 2008 Aug 17.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pathology and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, California 94143-0875, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/18716624" target="_blank"〉PubMed〈/a〉
    Keywords: Adenocarcinoma/genetics/metabolism/pathology/therapy ; Animals ; Gastrointestinal Tract/cytology/metabolism/pathology ; Genes, Dominant/genetics ; Genes, ras ; *Genetic Therapy ; Lung Neoplasms/genetics/metabolism/pathology/*therapy ; Male ; Mice ; *Models, Biological ; Mutation/genetics ; Oncogene Protein p21(ras)/metabolism ; Proto-Oncogene Proteins c-myc/*antagonists & inhibitors/*genetics/metabolism ; Skin/cytology/metabolism/pathology ; Testis/cytology/metabolism/pathology ; Transgenes/genetics
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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