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Ref Type Journal Article
PMID (34482287)
Authors O'Donohue TJ, Ibáñez G, Coutinho DF, Mauguen A, Siddiquee A, Rosales N, Calder P, Ndengu A, You D, Long M, Roberts SS, Kung AL, Dela Cruz FS
Title Translational Strategies for Repotrectinib in Neuroblastoma.
Journal Molecular cancer therapeutics
Vol 20
Issue 11
Date 2021 11
URL
Abstract Text 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. In vitro sensitivity to repotrectinib, ensartinib, and cytotoxic chemotherapy was evaluated in neuroblastoma cell lines. In vivo 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 ALK 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 (P < 0.05). Repotrectinib plus chemotherapy was superior to chemotherapy alone in ALK-mutant and ALK 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
ALK F1174V neuroblastoma predicted - sensitive Irinotecan + Repotrectinib + Temozolomide Preclinical - Pdx Actionable In a preclinical study, combination treatment with Repotrectinib (TPX-0005), Camptosar (irinotecan), and Temodar (temozolomide) resulted in inhibition of tumor growth in a patient-derived xenograft (PDX) model of neuroblastoma harboring ALK F1174V (PMID: 34482287). 34482287
ALK amp neuroblastoma predicted - sensitive Repotrectinib Case Reports/Case Series Actionable In a preclinical study, Repotrectinib (TPX-0005) treatment resulted in inhibition of cell proliferation in a neuroblastoma cell line harboring ALK amplification in culture (PMID: 34482287). 34482287
ALK F1174V neuroblastoma predicted - resistant Repotrectinib Preclinical - Pdx Actionable In a preclinical study, a neuroblastoma patient-derived xenograft (PDX) model harboring ALK F1174V was resistant to treatment with Repotrectinib (TPX-0005) (PMID: 34482287). 34482287
ALK R1275Q neuroblastoma predicted - sensitive Ensartinib Preclinical - Cell culture Actionable In a preclinical study, Ensartinib (X-396) treatment resulted in inhibition of cell proliferation in a neuroblastoma cell line harboring ALK R1275Q in culture (PMID: 34482287). 34482287
ALK amp neuroblastoma predicted - sensitive Ensartinib Preclinical - Cell culture Actionable In a preclinical study, Ensartinib (X-396) treatment resulted in inhibition of cell proliferation in a neuroblastoma cell line harboring ALK amplification in culture (PMID: 34482287). 34482287
ALK R1275Q neuroblastoma predicted - sensitive Repotrectinib Preclinical - Cell culture Actionable In a preclinical study, Repotrectinib (TPX-0005) treatment resulted in inhibition of cell proliferation in a neuroblastoma cell line harboring ALK R1275Q in culture (PMID: 34482287). 34482287