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  • Articles  (4)
  • Mutation/genetics  (4)
  • Nature Publishing Group (NPG)  (4)
  • Macmillian Magazines Ltd.
  • Physics  (4)
  • 1
    Publication Date: 2012-03-20
    Description: Targeted therapies have demonstrated efficacy against specific subsets of molecularly defined cancers. Although most patients with lung cancer are stratified according to a single oncogenic driver, cancers harbouring identical activating genetic mutations show large variations in their responses to the same targeted therapy. The biology underlying this heterogeneity is not well understood, and the impact of co-existing genetic mutations, especially the loss of tumour suppressors, has not been fully explored. Here we use genetically engineered mouse models to conduct a 'co-clinical' trial that mirrors an ongoing human clinical trial in patients with KRAS-mutant lung cancers. This trial aims to determine if the MEK inhibitor selumetinib (AZD6244) increases the efficacy of docetaxel, a standard of care chemotherapy. Our studies demonstrate that concomitant loss of either p53 (also known as Tp53) or Lkb1 (also known as Stk11), two clinically relevant tumour suppressors, markedly impaired the response of Kras-mutant cancers to docetaxel monotherapy. We observed that the addition of selumetinib provided substantial benefit for mice with lung cancer caused by Kras and Kras and p53 mutations, but mice with Kras and Lkb1 mutations had primary resistance to this combination therapy. Pharmacodynamic studies, including positron-emission tomography (PET) and computed tomography (CT), identified biological markers in mice and patients that provide a rationale for the differential efficacy of these therapies in the different genotypes. These co-clinical results identify predictive genetic biomarkers that should be validated by interrogating samples from patients enrolled on the concurrent clinical trial. These studies also highlight the rationale for synchronous co-clinical trials, not only to anticipate the results of ongoing human clinical trials, but also to generate clinically relevant hypotheses that can inform the analysis and design of human studies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3385933/" 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/PMC3385933/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Chen, Zhao -- Cheng, Katherine -- Walton, Zandra -- Wang, Yuchuan -- Ebi, Hiromichi -- Shimamura, Takeshi -- Liu, Yan -- Tupper, Tanya -- Ouyang, Jing -- Li, Jie -- Gao, Peng -- Woo, Michele S -- Xu, Chunxiao -- Yanagita, Masahiko -- Altabef, Abigail -- Wang, Shumei -- Lee, Charles -- Nakada, Yuji -- Pena, Christopher G -- Sun, Yanping -- Franchetti, Yoko -- Yao, Catherine -- Saur, Amy -- Cameron, Michael D -- Nishino, Mizuki -- Hayes, D Neil -- Wilkerson, Matthew D -- Roberts, Patrick J -- Lee, Carrie B -- Bardeesy, Nabeel -- Butaney, Mohit -- Chirieac, Lucian R -- Costa, Daniel B -- Jackman, David -- Sharpless, Norman E -- Castrillon, Diego H -- Demetri, George D -- Janne, Pasi A -- Pandolfi, Pier Paolo -- Cantley, Lewis C -- Kung, Andrew L -- Engelman, Jeffrey A -- Wong, Kwok-Kin -- 1U01CA141576/CA/NCI NIH HHS/ -- CA122794/CA/NCI NIH HHS/ -- CA137008/CA/NCI NIH HHS/ -- CA137008-01/CA/NCI NIH HHS/ -- CA137181/CA/NCI NIH HHS/ -- CA140594/CA/NCI NIH HHS/ -- CA147940/CA/NCI NIH HHS/ -- K23 CA157631/CA/NCI NIH HHS/ -- P01 CA120964/CA/NCI NIH HHS/ -- P30 CA016086/CA/NCI NIH HHS/ -- P50 CA090578/CA/NCI NIH HHS/ -- P50 CA090578-06/CA/NCI NIH HHS/ -- P50CA090578/CA/NCI NIH HHS/ -- R01 CA122794/CA/NCI NIH HHS/ -- R01 CA122794-01/CA/NCI NIH HHS/ -- R01 CA137008/CA/NCI NIH HHS/ -- R01 CA137008-01/CA/NCI NIH HHS/ -- R01 CA137181/CA/NCI NIH HHS/ -- R01 CA137181-01A2/CA/NCI NIH HHS/ -- R01 CA140594/CA/NCI NIH HHS/ -- R01 CA140594-01/CA/NCI NIH HHS/ -- R01 CA163896/CA/NCI NIH HHS/ -- RC2 CA147940/CA/NCI NIH HHS/ -- RC2 CA147940-01/CA/NCI NIH HHS/ -- U01 CA141576/CA/NCI NIH HHS/ -- U01 CA141576-01/CA/NCI NIH HHS/ -- England -- Nature. 2012 Mar 18;483(7391):613-7. doi: 10.1038/nature10937.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22425996" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Antineoplastic Combined Chemotherapy Protocols ; Benzimidazoles/*pharmacology/therapeutic use ; Biomarkers, Tumor/genetics/metabolism ; *Clinical Trials, Phase II as Topic ; *Disease Models, Animal ; Drug Evaluation, Preclinical ; Fluorodeoxyglucose F18 ; Genes, p53/genetics ; Humans ; Lung Neoplasms/*drug therapy/enzymology/*genetics/metabolism ; MAP Kinase Signaling System/drug effects ; Mice ; Mitogen-Activated Protein Kinase Kinases/antagonists & inhibitors ; Mutation/genetics ; Pharmacogenetics/*methods ; Positron-Emission Tomography ; Protein-Serine-Threonine Kinases/deficiency/genetics ; Proto-Oncogene Proteins/genetics/metabolism ; Proto-Oncogene Proteins p21(ras)/genetics/metabolism ; Randomized Controlled Trials as Topic ; Reproducibility of Results ; Taxoids/*therapeutic use ; Tomography, X-Ray Computed ; Treatment Outcome ; ras Proteins/genetics/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: 2014-07-22
    Description: Mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 are among the most common genetic alterations in intrahepatic cholangiocarcinoma (IHCC), a deadly liver cancer. Mutant IDH proteins in IHCC and other malignancies acquire an abnormal enzymatic activity allowing them to convert alpha-ketoglutarate (alphaKG) to 2-hydroxyglutarate (2HG), which inhibits the activity of multiple alphaKG-dependent dioxygenases, and results in alterations in cell differentiation, survival, and extracellular matrix maturation. However, the molecular pathways by which IDH mutations lead to tumour formation remain unclear. Here we show that mutant IDH blocks liver progenitor cells from undergoing hepatocyte differentiation through the production of 2HG and suppression of HNF-4alpha, a master regulator of hepatocyte identity and quiescence. Correspondingly, genetically engineered mouse models expressing mutant IDH in the adult liver show an aberrant response to hepatic injury, characterized by HNF-4alpha silencing, impaired hepatocyte differentiation, and markedly elevated levels of cell proliferation. Moreover, IDH and Kras mutations, genetic alterations that co-exist in a subset of human IHCCs, cooperate to drive the expansion of liver progenitor cells, development of premalignant biliary lesions, and progression to metastatic IHCC. These studies provide a functional link between IDH mutations, hepatic cell fate, and IHCC pathogenesis, and present a novel genetically engineered mouse model of IDH-driven malignancy.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4499230/" 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/PMC4499230/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Saha, Supriya K -- Parachoniak, Christine A -- Ghanta, Krishna S -- Fitamant, Julien -- Ross, Kenneth N -- Najem, Mortada S -- Gurumurthy, Sushma -- Akbay, Esra A -- Sia, Daniela -- Cornella, Helena -- Miltiadous, Oriana -- Walesky, Chad -- Deshpande, Vikram -- Zhu, Andrew X -- Hezel, Aram F -- Yen, Katharine E -- Straley, Kimberly S -- Travins, Jeremy -- Popovici-Muller, Janeta -- Gliser, Camelia -- Ferrone, Cristina R -- Apte, Udayan -- Llovet, Josep M -- Wong, Kwok-Kin -- Ramaswamy, Sridhar -- Bardeesy, Nabeel -- P50 CA127003/CA/NCI NIH HHS/ -- P50CA1270003/CA/NCI NIH HHS/ -- R01 CA136567/CA/NCI NIH HHS/ -- R01 DK098414/DK/NIDDK NIH HHS/ -- R01CA136567-02/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- England -- Nature. 2014 Sep 4;513(7516):110-4. doi: 10.1038/nature13441. Epub 2014 Jul 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉1] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2]. ; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA. ; Department of Medical Oncology, Dana-Farber Cancer Institute, Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA. ; 1] HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Catalonia 08036, Spain [2] Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA [3] Gastrointestinal Surgery and Liver Transplantation Unit, National Cancer Institute, and Department of Experimental Oncology, Milan 20133, Italy. ; HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Catalonia 08036, Spain. ; Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA. ; Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas 66160, USA. ; University of Rochester Medical Center, Rochester, New York 14642, USA. ; Agios Pharmaceuticals, Cambridge, Massachusetts 02139, USA. ; 1] HCC Translational Research Laboratory, Barcelona-Clinic Liver Cancer Group, Liver Unit, Institut d'Investigacions Biomediques August Pi i Sunyer (IDIBAPS), Hospital Clinic, University of Barcelona, Catalonia 08036, Spain [2] Mount Sinai Liver Cancer Program, Division of Liver Diseases, Dept of Medicine. Icahn School of Medicine at Mount Sinai, New York 10029, USA [3] Institucio Catalana de Recerca i Estudis Avancats, Barcelona, Catalonia 08010, Spain [4] University of Barcelona, Catalonia 08036, Spain. ; 1] Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA [2] Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25043045" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Bile Duct Neoplasms/enzymology/genetics/*pathology ; Bile Ducts, Intrahepatic/enzymology/pathology ; Cell Differentiation/*genetics ; Cell Division/genetics ; Cell Lineage/genetics ; Cholangiocarcinoma/enzymology/genetics/*pathology ; Disease Models, Animal ; Female ; Glutarates/metabolism ; Hepatocyte Nuclear Factor 4/*antagonists & ; inhibitors/biosynthesis/genetics/metabolism ; Hepatocytes/enzymology/metabolism/*pathology ; Humans ; Isocitrate Dehydrogenase/*genetics/metabolism ; Male ; Mice ; Mice, Transgenic ; Mutant Proteins/genetics/*metabolism ; Mutation/genetics ; Neoplasm Metastasis ; Proto-Oncogene Proteins/genetics/metabolism ; Stem Cells/pathology ; ras Proteins/genetics/metabolism
    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: 2011-06-28
    Description: Editing of the human genome to correct disease-causing mutations is a promising approach for the treatment of genetic disorders. Genome editing improves on simple gene-replacement strategies by effecting in situ correction of a mutant gene, thus restoring normal gene function under the control of endogenous regulatory elements and reducing risks associated with random insertion into the genome. Gene-specific targeting has historically been limited to mouse embryonic stem cells. The development of zinc finger nucleases (ZFNs) has permitted efficient genome editing in transformed and primary cells that were previously thought to be intractable to such genetic manipulation. In vitro, ZFNs have been shown to promote efficient genome editing via homology-directed repair by inducing a site-specific double-strand break (DSB) at a target locus, but it is unclear whether ZFNs can induce DSBs and stimulate genome editing at a clinically meaningful level in vivo. Here we show that ZFNs are able to induce DSBs efficiently when delivered directly to mouse liver and that, when co-delivered with an appropriately designed gene-targeting vector, they can stimulate gene replacement through both homology-directed and homology-independent targeted gene insertion at the ZFN-specified locus. The level of gene targeting achieved was sufficient to correct the prolonged clotting times in a mouse model of haemophilia B, and remained persistent after induced liver regeneration. Thus, ZFN-driven gene correction can be achieved in vivo, raising the possibility of genome editing as a viable strategy for the treatment of genetic disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3152293/" 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/PMC3152293/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Li, Hojun -- Haurigot, Virginia -- Doyon, Yannick -- Li, Tianjian -- Wong, Sunnie Y -- Bhagwat, Anand S -- Malani, Nirav -- Anguela, Xavier M -- Sharma, Rajiv -- Ivanciu, Lacramiora -- Murphy, Samuel L -- Finn, Jonathan D -- Khazi, Fayaz R -- Zhou, Shangzhen -- Paschon, David E -- Rebar, Edward J -- Bushman, Frederic D -- Gregory, Philip D -- Holmes, Michael C -- High, Katherine A -- P01 HL064190/HL/NHLBI NIH HHS/ -- P01 HL064190-11A1/HL/NHLBI NIH HHS/ -- T32 HL007150/HL/NHLBI NIH HHS/ -- T32 HL007150-35/HL/NHLBI NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2011 Jun 26;475(7355):217-21. doi: 10.1038/nature10177.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Hematology, CTRB 5000, Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, Philadelphia, Pennsylvania 19104, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21706032" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Base Sequence ; Cell Line, Tumor ; DNA Breaks, Double-Stranded ; DNA Repair/*genetics ; *Disease Models, Animal ; Endonucleases/chemistry/genetics/metabolism ; Exons/genetics ; Factor IX/analysis/genetics ; Gene Targeting/*methods ; Genetic Therapy/*methods ; Genetic Vectors/genetics ; Genome/*genetics ; HEK293 Cells ; Hemophilia B/*genetics/physiopathology ; *Hemostasis ; Humans ; Introns/genetics ; Liver/metabolism ; Liver Regeneration ; Mice ; Mice, Inbred C57BL ; Mutation/genetics ; Phenotype ; Sequence Homology ; Zinc Fingers
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 4
    Publication Date: 2011-08-26
    Description: Infections by the Ebola and Marburg filoviruses cause a rapidly fatal haemorrhagic fever in humans for which no approved antivirals are available. Filovirus entry is mediated by the viral spike glycoprotein (GP), which attaches viral particles to the cell surface, delivers them to endosomes and catalyses fusion between viral and endosomal membranes. Additional host factors in the endosomal compartment are probably required for viral membrane fusion; however, despite considerable efforts, these critical host factors have defied molecular identification. Here we describe a genome-wide haploid genetic screen in human cells to identify host factors required for Ebola virus entry. Our screen uncovered 67 mutations disrupting all six members of the homotypic fusion and vacuole protein-sorting (HOPS) multisubunit tethering complex, which is involved in the fusion of endosomes to lysosomes, and 39 independent mutations that disrupt the endo/lysosomal cholesterol transporter protein Niemann-Pick C1 (NPC1). Cells defective for the HOPS complex or NPC1 function, including primary fibroblasts derived from human Niemann-Pick type C1 disease patients, are resistant to infection by Ebola virus and Marburg virus, but remain fully susceptible to a suite of unrelated viruses. We show that membrane fusion mediated by filovirus glycoproteins and viral escape from the vesicular compartment require the NPC1 protein, independent of its known function in cholesterol transport. Our findings uncover unique features of the entry pathway used by filoviruses and indicate potential antiviral strategies to combat these deadly agents.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175325/" 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/PMC3175325/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Carette, Jan E -- Raaben, Matthijs -- Wong, Anthony C -- Herbert, Andrew S -- Obernosterer, Gregor -- Mulherkar, Nirupama -- Kuehne, Ana I -- Kranzusch, Philip J -- Griffin, April M -- Ruthel, Gordon -- Dal Cin, Paola -- Dye, John M -- Whelan, Sean P -- Chandran, Kartik -- Brummelkamp, Thijn R -- AI081842/AI/NIAID NIH HHS/ -- R01 AI081842/AI/NIAID NIH HHS/ -- R01 AI081842-03/AI/NIAID NIH HHS/ -- R01 AI088027/AI/NIAID NIH HHS/ -- R01 AI088027-03/AI/NIAID NIH HHS/ -- R21 HG004938/HG/NHGRI NIH HHS/ -- R21 HG004938-01/HG/NHGRI NIH HHS/ -- T32 AI070117/AI/NIAID NIH HHS/ -- T32 GM007288/GM/NIGMS NIH HHS/ -- U54 AI057159/AI/NIAID NIH HHS/ -- U54 AI057159-09/AI/NIAID NIH HHS/ -- England -- Nature. 2011 Aug 24;477(7364):340-3. doi: 10.1038/nature10348.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts 02142, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21866103" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Biological Transport ; Carrier Proteins/genetics/*metabolism ; Cell Line ; Cholesterol/*metabolism ; Ebolavirus/*physiology ; Endosomes/metabolism ; Fibroblasts/metabolism/pathology/virology ; Genome, Human/genetics ; Glycoproteins/metabolism ; Haploidy ; Hemorrhagic Fever, Ebola/drug therapy/metabolism ; Host-Pathogen Interactions/genetics ; Humans ; Lysosomes/metabolism ; Marburg Virus Disease/drug therapy/metabolism ; Marburgvirus/physiology ; Membrane Fusion/genetics/physiology ; Membrane Glycoproteins/deficiency/genetics/*metabolism ; Multiprotein Complexes/chemistry/deficiency/genetics/metabolism ; Mutation/genetics ; Niemann-Pick Diseases/pathology/virology ; Receptors, Virus/metabolism ; Viral Fusion Proteins/metabolism ; *Virus Internalization
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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