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; Kappler, Roland (2024): Drug prioritization identifies panobinostat as a tailored treatment element for patients with metastatic hepatoblastoma. Journal of Experimental & Clinical Cancer Research, 43: 299. ISSN 1756-9966

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.

• Dokumententyp: Artikel (Klinikum der LMU)
• Organisationseinheit (Fakultäten): 07 Medizin > Klinikum der LMU München > Kinderchirurgische Klinik und Poliklinik im Dr. von Haunerschen Kinderspital
• DFG-Fachsystematik der Wissenschaftsbereiche: Lebenswissenschaften
• DFG: Gefördert durch die Deutsche Forschungsgemeinschaft (DFG) - 491502892