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  • 1
    Publication Date: 2014-10-11
    Description: Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4636050/" 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/PMC4636050/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉de Bruin, Elza C -- McGranahan, Nicholas -- Mitter, Richard -- Salm, Max -- Wedge, David C -- Yates, Lucy -- Jamal-Hanjani, Mariam -- Shafi, Seema -- Murugaesu, Nirupa -- Rowan, Andrew J -- Gronroos, Eva -- Muhammad, Madiha A -- Horswell, Stuart -- Gerlinger, Marco -- Varela, Ignacio -- Jones, David -- Marshall, John -- Voet, Thierry -- Van Loo, Peter -- Rassl, Doris M -- Rintoul, Robert C -- Janes, Sam M -- Lee, Siow-Ming -- Forster, Martin -- Ahmad, Tanya -- Lawrence, David -- Falzon, Mary -- Capitanio, Arrigo -- Harkins, Timothy T -- Lee, Clarence C -- Tom, Warren -- Teefe, Enock -- Chen, Shann-Ching -- Begum, Sharmin -- Rabinowitz, Adam -- Phillimore, Benjamin -- Spencer-Dene, Bradley -- Stamp, Gordon -- Szallasi, Zoltan -- Matthews, Nik -- Stewart, Aengus -- Campbell, Peter -- Swanton, Charles -- 088340/Wellcome Trust/United Kingdom -- 091730/Wellcome Trust/United Kingdom -- 105104/Wellcome Trust/United Kingdom -- A11590/Cancer Research UK/United Kingdom -- A17786/Cancer Research UK/United Kingdom -- A19310/Cancer Research UK/United Kingdom -- A4688/Cancer Research UK/United Kingdom -- Cancer Research UK/United Kingdom -- Medical Research Council/United Kingdom -- New York, N.Y. -- Science. 2014 Oct 10;346(6206):251-6. doi: 10.1126/science.1253462.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. ; Cancer Research UK London Research Institute, London WC2A 3LY, UK. Centre for Mathematics and Physics in the Life Science and Experimental Biology (CoMPLEX), University College London, London WC1E 6BT, UK. ; Cancer Research UK London Research Institute, London WC2A 3LY, UK. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. University of Cambridge, Cambridge CB2 1TN, UK. ; Instituto de Biomedicina y Biotecnologia de Cantabria (CSIC-UC-Sodercan), Departamento de Biologia Molecular, Universidad de Cantabria, Santander, Spain. ; Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK. Department of Human Genetics, University of Leuven, 3000 Leuven, Belgium. ; Papworth Hospital NHS Foundation Trust, Cambridge CB23 3RE, UK. ; Lungs for Living Research Centre, University College London, London WC1E 6BT, UK. ; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. University College London Hospitals, London NW1 2BU, UK. ; University College London Hospitals, London NW1 2BU, UK. ; Thermo Fisher Scientific, Carlsbad, CA 92008, USA. ; Technical University of Denmark, 2800 Kongens Lyngby, Denmark. Children's Hospital Informatics Program, Harvard Medical School, Boston, MA 02115, USA. ; Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London WC1E 6BT, UK. Cancer Research UK London Research Institute, London WC2A 3LY, UK. charles.swanton@cancer.org.uk.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/25301630" target="_blank"〉PubMed〈/a〉
    Keywords: Carcinogens/toxicity ; Carcinoma, Non-Small-Cell Lung/chemically induced/*diagnosis/*genetics ; Cytidine Deaminase/genetics ; Evolution, Molecular ; Gene Dosage ; *Genetic Heterogeneity ; *Genomic Instability ; Humans ; Lung Neoplasms/chemically induced/*diagnosis/*genetics ; Mutation ; Neoplasm Recurrence, Local/genetics ; Prognosis ; Smoking/adverse effects ; Translocation, Genetic ; Tumor Cells, Cultured
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
    Publication Date: 2018-05-02
    Description: Purpose: This phase I, open-label study (Study 1, D3610C00001; NCT01226316) was the first-in-human evaluation of oral AZD5363, a selective pan-AKT inhibitor, in patients with advanced solid malignancies. The objectives were to investigate the safety, tolerability, and pharmacokinetics of AZD5363, define a recommended dosing schedule, and evaluate preliminary clinical activity. Experimental Design: Patients were aged ≥18 years with World Health Organization (WHO) performance status of 0 to 1. Dose escalation was conducted within separate continuous and intermittent [4 days/week (4/7) or 2 days/week (2/7)] schedules with safety, pharmacokinetic, and pharmacodynamic analyses. Expansion cohorts of approximately 20 patients each explored AZD5363 activity in PIK3CA -mutant breast and gynecologic cancers. Results: MTDs were 320, 480, and 640 mg for continuous ( n = 47), 4/7 ( n = 21), and 2/7 ( n = 22) schedules, respectively. Dose-limiting toxicities were rash and diarrhea for continuous, hyperglycemia for 2/7, and none for 4/7. Common adverse events were diarrhea (78%) and nausea (49%) and, for Common Terminology Criteria for Adverse Events grade ≥3 events, hyperglycemia (20%). The recommended phase II dose (480 mg bid, 4/7 intermittent) was assessed in PIK3CA -mutant breast and gynecologic expansion cohorts: 46% and 56% of patients, respectively, showed a reduction in tumor size, with RECIST responses of 4% and 8%. These responses were less than the prespecified 20% response rate; therefore, the criteria to stop further recruitment to the PIK3CA -mutant cohort were met. Conclusions: At the recommended phase II dose, AZD5363 was well tolerated and achieved plasma levels and robust target modulation in tumors. Proof-of-concept responses were observed in patients with PIK3CA -mutant cancers treated with AZD5363. Clin Cancer Res; 24(9); 2050–9. ©2017 AACR . See related commentary by Costa and Bosch, p. 2029
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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