Drug prioritization identifies panobinostat as a tailored treatment element for patients with metastatic hepatoblastoma.

Autor: Demir S; Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Lindwurmstreet 2a, Munich, 80337, Germany., Hotes A; Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Lindwurmstreet 2a, Munich, 80337, Germany., Schmid T; Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Lindwurmstreet 2a, Munich, 80337, Germany., Cairo S; XenTech, Evry, France.; Champions Oncology, Inc, Rockville, MD, USA., Indersie E; XenTech, Evry, France., Pisano C; Biogem, Institute of Molecular Biology and Genetics, Via Camporeale, Ariano Irpino, Italy., Hiyama E; Natural Science Center for Basic Research and Development, Hiroshima University, Hiroshima, Japan., Hishiki T; Department of Pediatric Surgery, Chiba University Graduate School of Medicine, Chiba, Japan., Vokuhl C; Institute of Pathology, University Hospital Bonn, Bonn, Germany., Branchereau S; Bicêtre Hospital, AP-HP Paris Saclay University, Paris, France., Brock P; Department of Paediatric Oncology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK., Schmid I; Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany., Zsiros J; Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands., Kappler R; Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, University Hospital, LMU Munich, Lindwurmstreet 2a, Munich, 80337, Germany. roland.kappler@med.uni-muenchen.de.
Jazyk: angličtina
Zdroj: Journal of experimental & clinical cancer research : CR [J Exp Clin Cancer Res] 2024 Nov 12; Vol. 43 (1), pp. 299. Date of Electronic Publication: 2024 Nov 12.
DOI: 10.1186/s13046-024-03221-6
Abstrakt: Background: Patients with metastatic hepatoblastoma are treated with severely toxic first-line chemotherapies in combination with surgery. Yet, inadequate response of lung metastases to neo-adjuvant chemotherapy still compromises patient outcomes making new treatment strategies, tailored to more efficient lung clearance, mandatory.
Methods: We harnessed a comprehensive patient-derived xenograft platform and a variety of in vitro and in vivo assays to establish the preclinical and biological rationale for a new drug for patients with metastatic hepatoblastoma.
Results: The testing of a library of established drugs on patient-derived xenografts identified histone deacetylase inhibitors, most notably panobinostat, to be highly efficacious on hepatoblastoma cells, as compared to non-cancerous cells. Molecularly, the anti-tumor effect of panobinostat is mediated by posttranslational obstruction of the MYC oncoprotein as a result of dual specificity phosphatase 1 upregulation, thereby leading to growth inhibition and programmed cell death. Of clinical importance, upregulation of the MYC target gene nucleophosmin 1 is indicative of response to panobinostat and associated with metastatic disease in patients with hepatoblastoma. The combination of panobinostat with the current SIOPEL 4 induction protocol, consisting of cisplatin and doxorubicin, revealed high synergies already at low nanomolar levels. The simulation of a clinical trial, with this combination therapy, in patient-derived xenograft models, and ultimately heterotypic lung metastasis mimics clearly underscored the potency of this approach.
Conclusion: Integrated studies define MYC inhibition by panobinostat as a novel treatment element to be introduced into the therapeutic strategy for patients with metastatic hepatoblastoma.
Competing Interests: Declarations Ethics approval and consent to participate In vivo testing in mice was carried out according to the Italian Decree (08/2023-UT). Consent for publication Not applicable. Competing interests The authors declare that they have no competing interests.
(© 2024. The Author(s).)
Databáze: MEDLINE
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