Translational Strategies for Repotrectinib in Neuroblastoma

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 a...

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Bibliographic Details
Published in:Molecular cancer therapeutics 2021-11, Vol.20 (11), p.2189-2197
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Humans
Macrocyclic Compounds - pharmacology
Macrocyclic Compounds - therapeutic use
Mice
Neuroblastoma - drug therapy
Neuroblastoma - pathology
Pyrazoles - pharmacology
Pyrazoles - therapeutic use
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Summary: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. sensitivity to repotrectinib, ensartinib, and cytotoxic chemotherapy was evaluated in neuroblastoma cell lines. antitumor effect of repotrectinib monotherapy, and in combination with chemotherapy, was evaluated using a genotypically diverse cohort of patient-derived xenograft (PDX) models of neuroblastoma. Repotrectinib had comparable cytotoxic activity across cell lines irrespective of mutational status. Combination with chemotherapy demonstrated increased antiproliferative activity across several cell lines. Repotrectinib monotherapy had notable antitumor activity and prolonged event-free survival compared with vehicle and ensartinib in PDX models ( < 0.05). Repotrectinib plus chemotherapy was superior to chemotherapy alone in -mutant and wild-type PDX models. These results demonstrate that repotrectinib has antitumor activity in genotypically diverse neuroblastoma models, and that combination of a multikinase inhibitor with chemotherapy may be a promising treatment paradigm for translation to the clinic.
ISSN:1535-7163
1538-8514
DOI:10.1158/1535-7163.MCT-21-0126