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  1. Article ; Online: Translational Strategies for Repotrectinib in Neuroblastoma.

    O'Donohue, Tara J / Ibáñez, Glorymar / Coutinho, Diego Ferreira / Mauguen, Audrey / Siddiquee, Armaan / Rosales, Nestor / Calder, Paul / Ndengu, Andoyo / You, Daoqi / Long, Matthew / Roberts, Stephen S / Kung, Andrew L / Dela Cruz, Filemon S

    Molecular cancer therapeutics

    2021  Volume 20, Issue 11, Page(s) 2189–2197

    Abstract: Limited clinical data are available regarding the utility of multikinase inhibition in neuroblastoma. Repotrectinib (TPX-0005) is a multikinase inhibitor that targets ALK, TRK, JAK2/STAT, and Src/FAK, which have all been implicated in the pathogenesis of ...

    Abstract Limited clinical data are available regarding the utility of multikinase inhibition in neuroblastoma. Repotrectinib (TPX-0005) is a multikinase inhibitor that targets ALK, TRK, JAK2/STAT, and Src/FAK, which have all been implicated in the pathogenesis of neuroblastoma. We evaluated the preclinical activity of repotrectinib monotherapy and in combination with chemotherapy as a potential therapeutic approach for relapsed/refractory neuroblastoma.
    MeSH term(s) Animals ; Humans ; Macrocyclic Compounds/pharmacology ; Macrocyclic Compounds/therapeutic use ; Mice ; Neuroblastoma/drug therapy ; Neuroblastoma/pathology ; Pyrazoles/pharmacology ; Pyrazoles/therapeutic use
    Chemical Substances Macrocyclic Compounds ; Pyrazoles ; repotrectinib (08O3FQ4UNP)
    Language English
    Publishing date 2021-09-04
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2063563-1
    ISSN 1538-8514 ; 1535-7163
    ISSN (online) 1538-8514
    ISSN 1535-7163
    DOI 10.1158/1535-7163.MCT-21-0126
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 5750: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
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    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)

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  2. Article ; Online: Subclonal Somatic Copy-Number Alterations Emerge and Dominate in Recurrent Osteosarcoma.

    Kinnaman, Michael D / Zaccaria, Simone / Makohon-Moore, Alvin / Arnold, Brian / Levine, Max F / Gundem, Gunes / Arango Ossa, Juan E / Glodzik, Dominik / Rodríguez-Sánchez, M Irene / Bouvier, Nancy / Li, Shanita / Stockfisch, Emily / Dunigan, Marisa / Cobbs, Cassidy / Bhanot, Umesh K / You, Daoqi / Mullen, Katelyn / Melchor, Jerry P / Ortiz, Michael V /
    O'Donohue, Tara J / Slotkin, Emily K / Wexler, Leonard H / Dela Cruz, Filemon S / Hameed, Meera R / Glade Bender, Julia L / Tap, William D / Meyers, Paul A / Papaemmanuil, Elli / Kung, Andrew L / Iacobuzio-Donahue, Christine A

    Cancer research

    2023  Volume 83, Issue 22, Page(s) 3796–3812

    Abstract: Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in ... ...

    Abstract Multiple large-scale genomic profiling efforts have been undertaken in osteosarcoma to define the genomic drivers of tumorigenesis, therapeutic response, and disease recurrence. The spatial and temporal intratumor heterogeneity could also play a role in promoting tumor growth and treatment resistance. We conducted longitudinal whole-genome sequencing of 37 tumor samples from 8 patients with relapsed or refractory osteosarcoma. Each patient had at least one sample from a primary site and a metastatic or relapse site. Subclonal copy-number alterations were identified in all patients except one. In 5 patients, subclones from the primary tumor emerged and dominated at subsequent relapses. MYC gain/amplification was enriched in the treatment-resistant clones in 6 of 7 patients with multiple clones. Amplifications in other potential driver genes, such as CCNE1, RAD21, VEGFA, and IGF1R, were also observed in the resistant copy-number clones. A chromosomal duplication timing analysis revealed that complex genomic rearrangements typically occurred prior to diagnosis, supporting a macroevolutionary model of evolution, where a large number of genomic aberrations are acquired over a short period of time followed by clonal selection, as opposed to ongoing evolution. A mutational signature analysis of recurrent tumors revealed that homologous repair deficiency (HRD)-related SBS3 increases at each time point in patients with recurrent disease, suggesting that HRD continues to be an active mutagenic process after diagnosis. Overall, by examining the clonal relationships between temporally and spatially separated samples from patients with relapsed/refractory osteosarcoma, this study sheds light on the intratumor heterogeneity and potential drivers of treatment resistance in this disease.
    Significance: The chemoresistant population in recurrent osteosarcoma is subclonal at diagnosis, emerges at the time of primary resection due to selective pressure from neoadjuvant chemotherapy, and is characterized by unique oncogenic amplifications.
    MeSH term(s) Humans ; Osteosarcoma/genetics ; Whole Genome Sequencing ; Genomics ; Bone Neoplasms/genetics ; Recurrence ; DNA Copy Number Variations ; Mutation
    Language English
    Publishing date 2023-10-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 1432-1
    ISSN 1538-7445 ; 0008-5472
    ISSN (online) 1538-7445
    ISSN 0008-5472
    DOI 10.1158/0008-5472.CAN-23-0385
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Uh III Zs.135/5: Show issues Location:
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    ab Jg. 2022: Lesesaal (EG)

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