Abstract A003: A novel treatment strategy for high-risk and relapse/refractory hepatoblastoma

Abstract Background: Patients with metastatic, treatment-refractory, and relapsed hepatoblastoma (HB) have survival rates of less than 50% due to limited treatment options. To better understand these aggressive phenotypes, our lab has developed a preclinical testing pipeline consisting of patient-derived spheroids (PDSp) and orthotopic xenograft models for chemotherapy and targeted therapy testing. We hypothesized that with this preclinical pipeline we could find an effective combination treatment strategy utilizing pan-histone deacetylase (HDAC) inhibition. Methods: RNA sequencing, microarray, NanoString, and immunohistochemistry (IHC) data of patient HB samples were analyzed for expression of all HDAC classes. HB cell lines were used to screen HDAC inhibitors. PDSp were used to screen which combination of standard chemotherapy regimens with a HDAC inhibitor. HB patient derived xenograft (PDX) mice models were developed and treated based off the lowest viability of PDSp drug screen. Mice were started on study when tumor volume reached 0.1-0.4 cm3 and were sacked when tumors reached diameter of 1.5 cm or at the end of the 6-week study period. Tumors were sectioned and evaluated for Ki67% and necrosis. Results: HDAC RNA and protein expression was elevated in HB tumors compared to normal livers. Four unique HB PDX models, including high risk, relapse and treatment refractory cases, were developed and validated from treatment-refractory patient tumors. Panobinostat (IC50 of 0.013-0.059 mM) showed strong in vitro effects with the lowest cell viability compared to other HDAC inhibitors. PDSp demonstrated the highest level of cell death with combination treatment of vincristine/irinotecan/panobinostat (VIP). After 6 week of treatment[SV1] , all four models had a limited response to VI therapy; however, showed a much improved response with VIP. All four models responded to therapy with a decrease in tumor size compared to placebo and survival to 6 weeks. Two of our four models that had showed some initial response to VI therapy demonstrated necrotic cell death, lower Ki67%, decreased serum alpha fetoprotein (AFP) and reduced tumor burden compared to paired vincristine/irinotecan (VI) and placebo. Conclusions: Utilizing a preclinical pipeline for HB, we have shown that panobinostat in combination with VI chemotherapy can induce an effective tumor response in models developed from high risk, relapse, and treatment refractory HB patients. This clinically relevant methodology can be used to screen novel targeted combination therapies with the VI backbone in order to create novel treatment strategies for future clinical trials. Citation Format: Andres F Espinoza, Roma Patel, Sai Govindu, Pavan Kureti, Bryan Armbruster, Sarah Woodfield, Sanjeev A Vasudevan. A novel treatment strategy for high-risk and relapse/refractory hepatoblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr A003.