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

Demir, Salih; Hotes, Alina; Schmid, Tanja; Cairo, Stefano; Indersie, Emilie; Pisano, Claudio; Hiyama, Eiso; Hishiki, Tomoro; Vokuhl, Christian; Branchereau, Sophie; Brock, Penelope; Schmid, Irene; Zsiros, József und Kappler, Roland (2024): Drug prioritization identifies panobinostat as a tailored treatment element for patients with metastatic hepatoblastoma. In: Journal of Experimental & Clinical Cancer Research, Vol. 43, 299

Abstract

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.

• Item Type: Journal article
• Faculties: Medicine > Medical Center of the University of Munich > Paediatric Surgery Clinic and Polyclinic in the Dr. von Hauner Children's Hospital
• Subjects: 600 Technology > 610 Medicine and health
• ISSN: 1756-9966
• Language: English
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892