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The screening of established drugs identifies histone deacetylase inhibition—especially panobinostat—as highly efficacious on hepatoblastoma cells versus noncancerous counterparts. Mechanistic work links antitumor activity to obstruction of MYC oncogenic signaling through dual specificity phosphatase 1 upregulation, producing growth inhibition and programmed cell death. A predictive MYC target response marker is described and panobinostat is shown to synergize with the SIOPEL 4 cisplatin/doxorubicin induction protocol at low nanomolar levels. 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J Exp Clin Cancer Res (2024) 43:299 [https://doi.org/10.1186/s13046-024-03221-6](https://doi.org/10.1186/s13046-024-03221-6)  \nJournal of Experimental & Clinical Cancer Research  \n RESEARCH Open Access  \nDrug prioritization identifies panobinostat  as a tailored treatment element for patients with metastatic hepatoblastoma  \nSalih Demir 1, Alina Hotes 1, Tanja Schmid1, Stefano Cairo2,3, Emilie Indersie2, Claudio Pisano4, Eiso Hiyama5, Tomoro Hishiki6, Christian Vokuhl7, Sophie Branchereau8, Penelope Brock9, Irene Schmid10, József Zsiros11 and Roland Kappler 1*  \nAbstract  \nBackground 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 noncancerous 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.  \nConclusion Integrated studies define MYC inhibition by panobinostat as a novel treatment element to be introduced into the therapeutic strategy for patients with metastatic hepatoblastoma.  \nKeywords Hepatoblastoma, Metastasis, Panobinostat, Therapy, MYC  \n*Correspondence:  \nRoland Kappler  \n[roland.kappler@med.uni-muenchen.de](roland.kappler@med.uni-muenchen.de)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[. The Creative Commons Public Domain Dedication waiver (](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ()[http://creativecom](http://creativecom)[mons.org/publicdomain/zero/1.0/](mons.org/publicdomain/zero/1.0/)) applies to the data made available in this article, unless otherwise stated in a credit line to the data.  \n","cbCaitDh1XhTcfv7","https://ap.wps.com/l/cbCaitDh1XhTcfv7","pdf",4715665,16,"English","# Abstract\n## Background\n## Methods\n## Results\n## Conclusion\n## Keywords","[{\"question\":\"What problem in metastatic hepatoblastoma drives the study’s need for new treatments?\",\"answer\":\"Metastatic lung disease often responds inadequately to neo-adjuvant first-line chemotherapy, compromising outcomes, and standard regimens carry severe toxicity with limited effective second-line or salvage options.\"},{\"question\":\"How was panobinostat identified as a candidate treatment?\",\"answer\":\"The study used a patient-derived xenograft platform to test a library of established drugs, finding histone deacetylase inhibitors—most notably panobinostat—to be highly efficacious on hepatoblastoma cells compared with noncancerous cells.\"},{\"question\":\"What mechanism and biomarkers connect panobinostat to antitumor effects?\",\"answer\":\"Panobinostat’s effect is mediated by posttranslational obstruction of the MYC oncoprotein via dual specificity phosphatase 1 upregulation, leading to growth inhibition and programmed cell death. Upregulation of the MYC target gene nucleophosmin 1 is presented as indicative of response and associated with metastatic disease.\"}]","Drug prioritization identifies panobinostat as a tailored treatment element for patients with metastatic hepatoblastoma | PDF",1789999232]