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      Precision medicine in pediatric oncology

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          Abstract

          Outcome in treatment of childhood cancers has improved dramatically since the 1970s. This success was largely achieved by the implementation of cooperative clinical research trial groups that standardized and developed treatment of childhood cancer. Nevertheless, outcome in certain types of malignancies is still unfavorable. Intensification of conventional chemotherapy and radiotherapy improved outcome only marginally at the cost of acute and long-term side effects. Hence, it is necessary to develop targeted therapy strategies.

          Here, we review the developments and perspectives in precision medicine in pediatric oncology with a special focus on targeted drug therapies like kinase inhibitors and inducers of apoptosis, the impact of cancer genome sequencing and immunotherapy.

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          Most cited references53

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          Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression.

          Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as 'occult cancer'. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use.
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            Limits to Personalized Cancer Medicine.

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              Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia

              There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden. Six pathways were frequently mutated, with NT5C2, CREBBP, WHSC1, TP53, USH2A, NRAS and IKZF1 mutations enriched at relapse. Half of the leukaemias had multiple subclonal mutations in a pathway or gene at diagnosis, but mostly with only one, usually minor clone, surviving therapy to acquire additional mutations and become the relapse founder clone. Relapse-specific mutations in NT5C2 were found in nine cases, with mutations in four cases being in descendants of the relapse founder clone. These results provide important insights into the genetic basis of treatment failure in ALL and have implications for the early detection of mutations driving relapse.
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                Author and article information

                Contributors
                stefan.burdach@tum.de
                andrew.westhoff@uniklinik-ulm.de
                maximilian.steinhauser@tum.de
                klaus-michael.debatin@uniklinik-ulm.de
                Journal
                Mol Cell Pediatr
                Mol Cell Pediatr
                Molecular and Cellular Pediatrics
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                2194-7791
                31 August 2018
                31 August 2018
                December 2018
                : 5
                : 6
                Affiliations
                [1 ]ISNI 0000000123222966, GRID grid.6936.a, Department of Pediatrics and Children’s Cancer Research Center (CCRC), , Technische Universität München, ; Koelner Platz 1, 80804 Munich, Germany
                [2 ]GRID grid.410712.1, Department of Pediatrics and Adolescent Medicine, , Ulm University Medical Center, ; Eythstr. 24, 89075 Ulm, Germany
                [3 ]CCC München-Comprehensive Cancer Center and German Translational Cancer Research Consortium (DKTK), Partner Site Munich, Munich, Germany
                Article
                84
                10.1186/s40348-018-0084-3
                6119176
                30171420
                c7c67058-3a28-438a-a824-1547f2d5403a
                © The Author(s). 2018

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                : 8 March 2018
                : 1 August 2018
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/100008672, Wilhelm Sander-Stiftung;
                Award ID: 2009.901.3
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100002347, Bundesministerium für Bildung und Forschung;
                Award ID: 01KT1311
                Award Recipient :
                Funded by: Cura Placida Children's Cancer Research Foundation
                Award ID: 6/2018
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2018

                childhood cancer,targeted drug therapies,immunotherapy,t-cell-based therapy

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