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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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  2. Article ; Online: Validation of a non-oncogene encoded vulnerability to exportin 1 inhibition in pediatric renal tumors.

    Coutinho, Diego F / Mundi, Prabhjot S / Marks, Lianna J / Burke, Chelsey / Ortiz, Michael V / Diolaiti, Daniel / Bird, Lauren / Vallance, Kelly L / Ibáñez, Glorymar / You, Daoqi / Long, Matthew / Rosales, Nestor / Grunn, Adina / Ndengu, Andoyo / Siddiquee, Armaan / Gaviria, Ervin S / Rainey, Allison R / Fazlollahi, Ladan / Hosoi, Hajime /
    Califano, Andrea / Kung, Andrew L / Dela Cruz, Filemon S

    Med (New York, N.Y.)

    2022  Volume 3, Issue 11, Page(s) 774–791.e7

    Abstract: Background: Malignant rhabdoid tumors (MRTs) and Wilms' tumors (WTs) are rare and aggressive renal tumors of infants and young children comprising ∼5% of all pediatric cancers. MRTs are among the most genomically stable cancers, and although WTs are ... ...

    Abstract Background: Malignant rhabdoid tumors (MRTs) and Wilms' tumors (WTs) are rare and aggressive renal tumors of infants and young children comprising ∼5% of all pediatric cancers. MRTs are among the most genomically stable cancers, and although WTs are genomically heterogeneous, both generally lack therapeutically targetable genetic mutations.
    Methods: Comparative protein activity analysis of MRTs (n = 68) and WTs (n = 132) across TCGA and TARGET cohorts, using metaVIPER, revealed elevated exportin 1 (XPO1) inferred activity. In vitro studies were performed on a panel of MRT and WT cell lines to evaluate effects on proliferation and cell-cycle progression following treatment with the selective XPO1 inhibitor selinexor. In vivo anti-tumor activity was assessed in patient-derived xenograft (PDX) models of MRTs and WTs.
    Findings: metaVIPER analysis identified markedly aberrant activation of XPO1 in MRTs and WTs compared with other tumor types. All MRT and most WT cell lines demonstrated baseline, aberrant XPO1 activity with in vitro sensitivity to selinexor via cell-cycle arrest and induction of apoptosis. In vivo, XPO1 inhibitors significantly abrogated tumor growth in PDX models, inducing effective disease control with sustained treatment. Corroborating human relevance, we present a case report of a child with multiply relapsed WTs with prolonged disease control on selinexor.
    Conclusions: We report on a novel systems-biology-based comparative framework to identify non-genetically encoded vulnerabilities in genomically quiescent pediatric cancers. These results have provided preclinical rationale for investigation of XPO1 inhibitors in an upcoming investigator-initiated clinical trial of selinexor in children with MRTs and WTs and offer opportunities for exploration of inferred XPO1 activity as a potential predictive biomarker for response.
    Funding: This work was funded by CureSearch for Children's Cancer, Alan B. Slifka Foundation, NIH (U01 CA217858, S10 OD012351, and S10 OD021764), Michael's Miracle Cure, Hyundai Hope on Wheels, Cannonball Kids Cancer, Conquer Cancer the ASCO Foundation, Cycle for Survival, Paulie Strong Foundation, and the Grayson Fund.
    MeSH term(s) Child ; Humans ; Child, Preschool ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Kidney Neoplasms/drug therapy ; Exportin 1 Protein
    Chemical Substances selinexor (31TZ62FO8F)
    Language English
    Publishing date 2022-10-03
    Publishing country United States
    Document type Case Reports ; Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ISSN 2666-6340
    ISSN (online) 2666-6340
    DOI 10.1016/j.medj.2022.09.002
    Database MEDical Literature Analysis and Retrieval System OnLINE

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