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Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Children’s Oncology Group (COG) New Agents for Ewing Sarcoma Task Force

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      Abstract

      Ewing sarcoma is a small round blue cell malignancy arising from bone or soft tissue and most commonly affects adolescents and young adults. Metastatic and relapsed Ewing sarcoma have poor outcomes and recurrences remain common. Owing to the poor outcomes associated with advanced disease and the need for a clear research strategy, the Children’s Oncology Group Bone Tumor Committee formed the New Agents for Ewing Sarcoma Task Force to bring together experts in the field to evaluate and prioritize new agents for incorporation into clinical trials. This group’s mission was to evaluate scientific and clinical challenges in moving new agents forward and to recommend agents and trial designs to the Bone Tumor Committee. The task force generated a framework for vetting prospective agents that included critical evaluation of each drug by using both clinical and non-clinical parameters. Representative appraisal of agents of highest priority, including eribulin, dinutuximab, cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors, anti-angiogenic tyrosine kinase inhibitors, and poly-ADP-ribose polymerase (PARP) inhibitors, is described. The task force continues to analyze new compounds by using the paradigm established.

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      Systematic identification of genomic markers of drug sensitivity in cancer cells

      Clinical responses to anticancer therapies are often restricted to a subset of patients. In some cases, mutated cancer genes are potent biomarkers of response to targeted agents. To uncover new biomarkers of sensitivity and resistance to cancer therapeutics, we screened a panel of several hundred cancer cell lines, which represent much of the tissue-type and genetic diversity of human cancers, with 130 drugs under clinical and preclinical investigation. In aggregate, we found mutated cancer genes were associated with cellular response to most currently available cancer drugs. Classic oncogene addiction paradigms were modified by additional tissue-specific or expression biomarkers, and some frequently mutated genes were associated with sensitivity to a broad range of therapeutic agents. Unexpected relationships were revealed, including the marked sensitivity of Ewing’s sarcoma cells harboring the EWS-FLI1 gene translocation to PARP inhibitors. By linking drug activity to the functional complexity of cancer genomes, systematic pharmacogenomic profiling in cancer cell lines provides a powerful biomarker discovery platform to guide rational cancer therapeutic strategies.
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        Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial.

        Pazopanib, a multitargeted tyrosine kinase inhibitor, has single-agent activity in patients with advanced non-adipocytic soft-tissue sarcoma. We investigated the effect of pazopanib on progression-free survival in patients with metastatic non-adipocytic soft-tissue sarcoma after failure of standard chemotherapy. This phase 3 study was done in 72 institutions, across 13 countries. Patients with angiogenesis inhibitor-naive, metastatic soft-tissue sarcoma, progressing despite previous standard chemotherapy, were randomly assigned by an interactive voice randomisation system in a 2:1 ratio in permuted blocks (with block sizes of six) to receive either pazopanib 800 mg once daily or placebo, with no subsequent cross-over. Patients, investigators who gave the treatment, those assessing outcomes, and those who did the analysis were masked to the allocation. The primary endpoint was progression-free survival. Efficacy analysis was by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00753688. 372 patients were registered and 369 were randomly assigned to receive pazopanib (n=246) or placebo (n=123). Median progression-free survival was 4·6 months (95% CI 3·7-4·8) for pazopanib compared with 1·6 months (0·9-1·8) for placebo (hazard ratio [HR] 0·31, 95% CI 0·24-0·40; p<0·0001). Overall survival was 12·5 months (10·6-14·8) with pazopanib versus 10·7 months (8·7-12·8) with placebo (HR 0·86, 0·67-1·11; p=0·25). The most common adverse events were fatigue (60 in the placebo group [49%] vs 155 in the pazopanib group [65%]), diarrhoea (20 [16%] vs 138 [58%]), nausea (34 [28%] vs 129 [54%]), weight loss (25 [20%] vs 115 [48%]), and hypertension (8 [7%] vs 99 [41%]). The median relative dose intensity was 100% for placebo and 96% for pazopanib. Pazopanib is a new treatment option for patients with metastatic non-adipocytic soft-tissue sarcoma after previous chemotherapy. GlaxoSmithKline. Copyright © 2012 Elsevier Ltd. All rights reserved.
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          A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.

          The division cycle of eukaryotic cells is regulated by a family of protein kinases known as the cyclin-dependent kinases (CDKs). The sequential activation of individual members of this family and their consequent phosphorylation of critical substrates promotes orderly progression through the cell cycle. The complexes formed by CDK4 and the D-type cyclins have been strongly implicated in the control of cell proliferation during the G1 phase. CDK4 exists, in part, as a multi-protein complex with a D-type cyclin, proliferating cell nuclear antigen and a protein, p21 (refs 7-9). CDK4 associates separately with a protein of M(r) 16K, particularly in cells lacking a functional retinoblastoma protein. Here we report the isolation of a human p16 complementary DNA and demonstrate that p16 binds to CDK4 and inhibits the catalytic activity of the CDK4/cyclin D enzymes. p16 seems to act in a regulatory feedback circuit with CDK4, D-type cyclins and retinoblastoma protein.
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            Author and article information

            Affiliations
            [1 ]Division of Pediatric Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
            [2 ]Center for Cancer and Blood Disorders, Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA
            [3 ]Departments of Pediatrics and Genetics, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA
            [4 ]Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
            [5 ]Departement of Pediatrics, Van Andel Institute, Helen De Vos Children’s Hospital and Michigan State University, Grand Rapids, MI, USA
            [6 ]Greehey Children’s Cancer Research Institute, University of Texas Health Science Center, San Antonio, TX, USA
            [7 ]Center for Cancer and Blood Disorders, Connecticut Children’s Medical Center, Hartford, CT, USA
            [8 ]Department of Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
            [9 ]Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA
            [10 ]The Faris D. Virani Ewing Sarcoma Center at the Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX, USA
            [11 ]AYA Program, Moffitt Cancer Center, Tampa, FL, USA
            [12 ]Johns Hopkins All Children’s Hospital, St. Petersburg, FL, USA
            [13 ]Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Harvard Medical School, Boston, MA, USA
            [14 ]Division of Pediatrics, University of Texas MD Anderson Cancer Center, Houston, TX, USA
            [15 ]Center for Childhood Cancer and Blood Diseases, Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
            [16 ]Division of Pediatric Hematology/Oncology/Bone Marrow Transplantation, The Ohio State University College of Medicine, Columbus, OH, USA
            [17 ]Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, AZ, USA
            Author notes

            No competing interests were disclosed.

            Contributors
            Role: Conceptualization, Role: Methodology, Role: Visualization, Role: Writing – Original Draft Preparation, Role: Writing – Review & Editing, ORCID: https://orcid.org/0000-0003-3925-3243
            Role: Conceptualization, Role: Methodology, Role: Visualization, Role: Writing – Original Draft Preparation, Role: Writing – Review & Editing
            Role: Methodology, Role: Writing – Review & Editing
            Role: Methodology, Role: Writing – Review & Editing
            Role: Methodology, Role: Writing – Review & Editing
            Role: Methodology, Role: Writing – Review & Editing
            Role: Methodology, Role: Writing – Review & Editing
            Role: Methodology, Role: Writing – Review & Editing
            Role: Methodology, Role: Writing – Review & Editing
            Role: Methodology, Role: Writing – Review & Editing
            Role: Methodology, Role: Writing – Review & Editing
            Role: Writing – Review & Editing
            Role: Writing – Review & Editing
            Role: Methodology, Role: Project Administration, Role: Supervision, Role: Writing – Review & Editing
            Role: Conceptualization, Role: Methodology, Role: Project Administration, Role: Supervision, Role: Visualization, Role: Writing – Review & Editing
            Role: Conceptualization, Role: Methodology, Role: Project Administration, Role: Supervision, Role: Visualization, Role: Writing – Review & Editing
            Journal
            F1000Res
            F1000Res
            F1000Research
            F1000Research
            F1000 Research Limited (London, UK )
            2046-1402
            15 April 2019
            2019
            : 8
            6468706
            10.12688/f1000research.18139.1
            Copyright: © 2019 Bailey K et al.

            This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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            Funding
            Funded by: NCTN Operations Center Grant
            Award ID: U10CA180886
            This work is supported by the Children’s Oncology Group and the National Cancer Institute of the National Institutes of Health under NCTN Operations Center Grant U10CA180886.
            The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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