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author Tucker, Elizabeth R.
Jiménez, Irene
Chen, Lindi
Bellini, Angela
Gorrini, Chiara
Calton, Elizabeth
Gao, Qiong
Che, Harvey
Poon, Evon
Jamin, Yann
Martins Da Costa, Barbara
Barker, Karen
Shrestha, Sumana
Hutchinson, J. Ciaran
Dhariwal, Simran
Goodman, Angharad
Del Nery, Elaine
Gestraud, Pierre
Bhalshankar, Jaydutt
Iddir, Yasmine
Saberi-Ansari, Elnaz
Saint-Charles, Alexandra
Geoerger, Birgit
Marques Da Costa, Maria Eugénia
Pierre-Eugène, Cécile
Janoueix-Lerosey, Isabelle
Decaudin, Didier
Nemati, Fariba
Carcaboso, Angel M.
Surdez, Didier
Delattre, Olivier
George, Sally L.
Chesler, Louis
Tweddle, Deborah A.
Schleiermacher, Gudrun
author_facet Tucker, Elizabeth R.
Jiménez, Irene
Chen, Lindi
Bellini, Angela
Gorrini, Chiara
Calton, Elizabeth
Gao, Qiong
Che, Harvey
Poon, Evon
Jamin, Yann
Martins Da Costa, Barbara
Barker, Karen
Shrestha, Sumana
Hutchinson, J. Ciaran
Dhariwal, Simran
Goodman, Angharad
Del Nery, Elaine
Gestraud, Pierre
Bhalshankar, Jaydutt
Iddir, Yasmine
Saberi-Ansari, Elnaz
Saint-Charles, Alexandra
Geoerger, Birgit
Marques Da Costa, Maria Eugénia
Pierre-Eugène, Cécile
Janoueix-Lerosey, Isabelle
Decaudin, Didier
Nemati, Fariba
Carcaboso, Angel M.
Surdez, Didier
Delattre, Olivier
George, Sally L.
Chesler, Louis
Tweddle, Deborah A.
Schleiermacher, Gudrun
author_sort Tucker, Elizabeth R.
collection PubMed
description PURPOSE: ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%–2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. EXPERIMENTAL DESIGN: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX). RESULTS: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. CONCLUSIONS: In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma.
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spelling pubmed-100684372023-04-04 Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models Tucker, Elizabeth R. Jiménez, Irene Chen, Lindi Bellini, Angela Gorrini, Chiara Calton, Elizabeth Gao, Qiong Che, Harvey Poon, Evon Jamin, Yann Martins Da Costa, Barbara Barker, Karen Shrestha, Sumana Hutchinson, J. Ciaran Dhariwal, Simran Goodman, Angharad Del Nery, Elaine Gestraud, Pierre Bhalshankar, Jaydutt Iddir, Yasmine Saberi-Ansari, Elnaz Saint-Charles, Alexandra Geoerger, Birgit Marques Da Costa, Maria Eugénia Pierre-Eugène, Cécile Janoueix-Lerosey, Isabelle Decaudin, Didier Nemati, Fariba Carcaboso, Angel M. Surdez, Didier Delattre, Olivier George, Sally L. Chesler, Louis Tweddle, Deborah A. Schleiermacher, Gudrun Clin Cancer Res Translational Cancer Mechanisms and Therapy PURPOSE: ALK-activating mutations are identified in approximately 10% of newly diagnosed neuroblastomas and ALK amplifications in a further 1%–2% of cases. Lorlatinib, a third-generation anaplastic lymphoma kinase (ALK) inhibitor, will soon be given alongside induction chemotherapy for children with ALK-aberrant neuroblastoma. However, resistance to single-agent treatment has been reported and therapies that improve the response duration are urgently required. We studied the preclinical combination of lorlatinib with chemotherapy, or with the MDM2 inhibitor, idasanutlin, as recent data have suggested that ALK inhibitor resistance can be overcome through activation of the p53-MDM2 pathway. EXPERIMENTAL DESIGN: We compared different ALK inhibitors in preclinical models prior to evaluating lorlatinib in combination with chemotherapy or idasanutlin. We developed a triple chemotherapy (CAV: cyclophosphamide, doxorubicin, and vincristine) in vivo dosing schedule and applied this to both neuroblastoma genetically engineered mouse models (GEMM) and patient-derived xenografts (PDX). RESULTS: Lorlatinib in combination with chemotherapy was synergistic in immunocompetent neuroblastoma GEMM. Significant growth inhibition in response to lorlatinib was only observed in the ALK-amplified PDX model with high ALK expression. In this PDX, lorlatinib combined with idasanutlin resulted in complete tumor regression and significantly delayed tumor regrowth. CONCLUSIONS: In our preclinical neuroblastoma models, high ALK expression was associated with lorlatinib response alone or in combination with either chemotherapy or idasanutlin. The synergy between MDM2 and ALK inhibition warrants further evaluation of this combination as a potential clinical approach for children with neuroblastoma. American Association for Cancer Research 2023-04-03 2023-01-05 /pmc/articles/PMC10068437/ /pubmed/36602782 http://dx.doi.org/10.1158/1078-0432.CCR-22-2274 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Translational Cancer Mechanisms and Therapy
Tucker, Elizabeth R.
Jiménez, Irene
Chen, Lindi
Bellini, Angela
Gorrini, Chiara
Calton, Elizabeth
Gao, Qiong
Che, Harvey
Poon, Evon
Jamin, Yann
Martins Da Costa, Barbara
Barker, Karen
Shrestha, Sumana
Hutchinson, J. Ciaran
Dhariwal, Simran
Goodman, Angharad
Del Nery, Elaine
Gestraud, Pierre
Bhalshankar, Jaydutt
Iddir, Yasmine
Saberi-Ansari, Elnaz
Saint-Charles, Alexandra
Geoerger, Birgit
Marques Da Costa, Maria Eugénia
Pierre-Eugène, Cécile
Janoueix-Lerosey, Isabelle
Decaudin, Didier
Nemati, Fariba
Carcaboso, Angel M.
Surdez, Didier
Delattre, Olivier
George, Sally L.
Chesler, Louis
Tweddle, Deborah A.
Schleiermacher, Gudrun
Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models
title Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models
title_full Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models
title_fullStr Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models
title_full_unstemmed Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models
title_short Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models
title_sort combination therapies targeting alk-aberrant neuroblastoma in preclinical models
topic Translational Cancer Mechanisms and Therapy
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10068437/
https://www.ncbi.nlm.nih.gov/pubmed/36602782
http://dx.doi.org/10.1158/1078-0432.CCR-22-2274
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