Combination Therapies Targeting ALK-aberrant Neuroblastoma in Preclinical Models.

Autor:	Tucker ER; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Jiménez I; SiRIC RTOP (Recherche Translationelle en Oncologie Pédiatrique), Translational Research Department, Institut Curie Research Center, PSL Research University, Institut Curie, Paris, France.; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France., Chen L; Wolfson Childhood Cancer Research Centre, Translational & Clinical Research Institute, Newcastle Centre for Cancer, Newcastle University, Newcastle upon Tyne, United Kingdom., Bellini A; SiRIC RTOP (Recherche Translationelle en Oncologie Pédiatrique), Translational Research Department, Institut Curie Research Center, PSL Research University, Institut Curie, Paris, France.; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France., Gorrini C; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Calton E; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Gao Q; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Che H; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Poon E; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Jamin Y; Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom., Martins Da Costa B; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Barker K; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Shrestha S; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Hutchinson JC; Department of Histopathology, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom., Dhariwal S; Wolfson Childhood Cancer Research Centre, Translational & Clinical Research Institute, Newcastle Centre for Cancer, Newcastle University, Newcastle upon Tyne, United Kingdom., Goodman A; Newcastle Genetics Laboratory, Newcastle upon Tyne Hospitals NHS Trust, Newcastle upon Tyne, United Kingdom., Del Nery E; Department of Translational Research, The Biophenics High-Content Screening Laboratory, PSL Research University, PICT-IBiSa, Institut Curie Research Center, Paris, France., Gestraud P; Bioinformatics platform, INSERM U900, PSL Research University, Institut Curie Research Center, Paris, France., Bhalshankar J; SiRIC RTOP (Recherche Translationelle en Oncologie Pédiatrique), Translational Research Department, Institut Curie Research Center, PSL Research University, Institut Curie, Paris, France.; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France., Iddir Y; SiRIC RTOP (Recherche Translationelle en Oncologie Pédiatrique), Translational Research Department, Institut Curie Research Center, PSL Research University, Institut Curie, Paris, France.; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France., Saberi-Ansari E; SiRIC RTOP (Recherche Translationelle en Oncologie Pédiatrique), Translational Research Department, Institut Curie Research Center, PSL Research University, Institut Curie, Paris, France.; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France., Saint-Charles A; SiRIC RTOP (Recherche Translationelle en Oncologie Pédiatrique), Translational Research Department, Institut Curie Research Center, PSL Research University, Institut Curie, Paris, France.; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France., Geoerger B; Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Université Paris-Saclay, Villejuif, France., Marques Da Costa ME; Gustave Roussy Cancer Center, Department of Pediatric and Adolescent Oncology, Université Paris-Saclay, Villejuif, France., Pierre-Eugène C; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France., Janoueix-Lerosey I; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France., Decaudin D; Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, Paris, France.; Department of Medical Oncology, Institut Curie, Paris, France., Nemati F; Laboratory of Preclinical Investigation, Department of Translational Research, Institut Curie, PSL University, Paris, France., Carcaboso AM; Hospital Sant Joan de Déu, Barcelona, Spain., Surdez D; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France.; Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland., Delattre O; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France., George SL; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Chesler L; Pediatric Tumour Biology and Therapeutics Team, Centre for Paediatric Oncology Experimental Medicine, Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom., Tweddle DA; Wolfson Childhood Cancer Research Centre, Translational & Clinical Research Institute, Newcastle Centre for Cancer, Newcastle University, Newcastle upon Tyne, United Kingdom., Schleiermacher G; SiRIC RTOP (Recherche Translationelle en Oncologie Pédiatrique), Translational Research Department, Institut Curie Research Center, PSL Research University, Institut Curie, Paris, France.; INSERM U830, Equipe Labellisée Ligue contre le Cancer, PSL Research University, Institut Curie Research Center, Paris, France.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2023 Apr 03; Vol. 29 (7), pp. 1317-1331.
DOI:	10.1158/1078-0432.CCR-22-2274
Abstrakt:	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. (©2023 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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