Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma.

Autor:	Duchatel RJ; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Mannan A; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Woldu AS; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Hawtrey T; School of Chemistry, University of New South Wales, Sydney, New South Wales, Australia., Hindley PA; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Jewells Medical Centre, Jewells, New South Wales, Australia., Douglas AM; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Jackson ER; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Findlay IJ; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Germon ZP; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Staudt D; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Kearney PS; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia., Smith ND; Analytical and Biomolecular Research Facility, Advanced Mass Spectrometry Unit, University of Newcastle, Callaghan, New South Wales, Australia., Hindley KE; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Sash Small Animal Specialist Hospital, Tuggerah, New South Wales, Australia., Cain JE; Hudson Institute of Medical Research, Clayton, Victoria, Australia.; Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia., André N; Department of Pediatric Oncology, La Timone Children's Hospital, AP-HM, Marseille, France.; SMARTc Unit, Centre de Recherche en Cancérologie de Marseille, Inserm U1068, Aix Marseille Univ, Marseille, France., La Madrid AM; Laboratory of Developmental Cancer, Institut de Recerca Sant Joan de Déu, Barcelona, Spain.; Department of Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.; Neuro-Oncology Unit, Hospital Sant Joan de Déu, Barcelona, Spain., Nixon B; Reproductive Science Group, College of Engineering, Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia., De Iuliis GN; Reproductive Science Group, College of Engineering, Science and Environment, University of Newcastle, Callaghan, New South Wales, Australia., Nazarian J; Children's National Medical Center, Washington, District of Columbia., USA.; University Children's Hospital Zurich, Zurich, Switzerland., Irish K; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.; John Hunter Children's Hospital, New Lambton Heights, New South Wales, Australia., Alvaro F; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.; John Hunter Children's Hospital, New Lambton Heights, New South Wales, Australia., Eisenstat DD; Children's Cancer Centre, The Royal Children's Hospital Melbourne, Parkville, Victoria, Australia.; Neuro-Oncology Laboratory, Murdoch Children's Research Institute, Parkville, Victoria, Australia.; Department of Paediatrics, University of Melbourne, Parkville, Victoria, Australia., Beck A; Center for Neuropathology, Ludwig Maximilian University of Munich, Munich, Germany., Vitanza NA; Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington, USA.; Division of Pediatric Hematology/Oncology, Department of Pediatrics, Seattle Children's Hospital, Seattle, Washington, USA., Mueller S; University Children's Hospital Zurich, Zurich, Switzerland.; Department of Neurology, Neurosurgery and Pediatrics, University of California, San Francisco, California, USA., Morris JC; School of Chemistry, University of New South Wales, Sydney, New South Wales, Australia., Dun MD; Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, New South Wales, Australia.; Hunter Medical Research Institute, New Lambton Heights, New South Wales, Australia.
Jazyk:	angličtina
Zdroj:	Neuro-oncology advances [Neurooncol Adv] 2021 Nov 19; Vol. 3 (1), pp. vdab169. Date of Electronic Publication: 2021 Nov 19 (Print Publication: 2021).
DOI:	10.1093/noajnl/vdab169
Abstrakt:	Background: Diffuse intrinsic pontine glioma (DIPG) is a fatal childhood brainstem tumor for which radiation is the only treatment. Case studies report a clinical response to ONC201 for patients with H3K27M-mutant gliomas. Oncoceutics (ONC201) is only available in the United States and Japan; however, in Germany, DIPG patients can be prescribed and dispensed a locally produced compound-ONC201 German-sourced ONC201 (GsONC201). Pediatric oncologists face the dilemma of supporting the administration of GsONC201 as conjecture surrounds its authenticity. Therefore, we compared GsONC201 to original ONC201 manufactured by Oncoceutics Inc. Methods: Authenticity of GsONC201 was determined by high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy. Biological activity was shown via assessment of on-target effects, in vitro growth, proliferation, and apoptosis analysis. Patient-derived xenograft mouse models were used to assess plasma and brain tissue pharmacokinetics, pharmacodynamics, and overall survival (OS). The clinical experience of 28 H3K27M+ mutant DIPG patients who received GsONC201 (2017-2020) was analyzed. Results: GsONC201 harbored the authentic structure, however, was formulated as a free base rather than the dihydrochloride salt used in clinical trials. GsONC201 in vitro and in vivo efficacy and drug bioavailability studies showed no difference compared to Oncoceutics ONC201. Patients treated with GsONC201 (n = 28) showed a median OS of 18 months ( P = .0007). GsONC201 patients who underwent reirradiation showed a median OS of 22 months compared to 12 months for GsONC201 patients who did not ( P = .012). Conclusions: This study confirms the biological activity of GsONC201 and documents the OS of patients who received the drug; however, GsONC201 was never used as a monotherapy. (© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.)
Databáze:	MEDLINE
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