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Great challenges in molecular medicine: toward personalized medicine

Frontiers in Cell and Developmental Biology

Frontiers Media S.A.

bio-bank, database, knowledgebase, clinical sequencing, big data, WNT, FGF, Hedgehog

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      Wnt/beta-catenin signaling in development and disease.

       Hans Clevers (2006)
      A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades. Wnt genes encode small secreted proteins that are found in all animal genomes. Wnt signaling is involved in virtually every aspect of embryonic development and also controls homeostatic self-renewal in a number of adult tissues. Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.
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        Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.

        Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).
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          A decade of exploring the cancer epigenome - biological and translational implications.

          The past decade has highlighted the central role of epigenetic processes in cancer causation, progression and treatment. Next-generation sequencing is providing a window for visualizing the human epigenome and how it is altered in cancer. This view provides many surprises, including linking epigenetic abnormalities to mutations in genes that control DNA methylation, the packaging and the function of DNA in chromatin, and metabolism. Epigenetic alterations are leading candidates for the development of specific markers for cancer detection, diagnosis and prognosis. The enzymatic processes that control the epigenome present new opportunities for deriving therapeutic strategies designed to reverse transcriptional abnormalities that are inherent to the cancer epigenome.
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            Author and article information

            Affiliations
            Katoh's Unit, National Cancer Center Tokyo, Japan
            Author notes

            This article was submitted to Molecular Medicine, a section of the journal Frontiers in Cell and Developmental Biology.

            Edited by: Craig M. Walsh, University of California, Irvine, USA

            Journal
            Front Cell Dev Biol
            Front Cell Dev Biol
            Front. Cell Dev. Biol.
            Frontiers in Cell and Developmental Biology
            Frontiers Media S.A.
            2296-634X
            04 October 2013
            2013
            : 1
            4207013
            10.3389/fcell.2013.00001
            Copyright © 2013 Katoh.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

            Counts
            Figures: 1, Tables: 0, Equations: 0, References: 47, Pages: 4, Words: 3470
            Categories
            Cell and Developmental Biology
            Specialty Grand Challenge Article

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