54P Targeted treatment options for childhood hepatoblastoma using high-throughput drug screening

Abstract

Hepatoblastoma (HB) is a pediatric malignancy with prevalence of 1:1 000 000 in Europe. Median age at diagnosis is one year. Current treatment entails chemotherapy (platinum-based alone or combined with doxorubicin) followed by surgery (tumor resection or liver transplantation). Survival rate of HB patients has improved; however, high-risk HB tumors are still difficult to treat with 20-30% of HB patients responding poorly to current treatment modalities. Furthermore, while current treatment modalities improve the prognosis, side effects of the chemotherapeutics have a significant effect on the life quality of HB survivors. Therefore, safer, more effective, and targeted treatment options are needed for improved patient care. Drug sensitivity and resistance testing (DSRT) was completed using 3D spheroids of five histologically different high-risk hepatoblastoma PDX-derived models. Cells were cultured with 527 approved or emerging oncological compounds and 1 drug combination for 72 h in five concentrations. Viability was assessed with Cell-Titer Glo. Pediatric primary hepatocytes were used to evaluate the general toxicity of the compounds. Selective drug sensitivity score (sDSS, calculated DSS(PDX) - DSS(control)) was calculated for each drug. sDSS score was used to evaluate the efficacy and tumor-sensitivity of each compound. Between 14 and 71 compounds with sDSS > 10 were identified for each HB model. These compounds represent a wide range of mechanisms of action and include kinase inhibitors, HSP inhibitors, apoptotic modulators, as well as conventional chemotherapeutics. Of these, 8 compounds were found to be effective in all five HB models. These were onalespib (a heat shock protein inhibitor (HSPI)), fimepinostat (PI3K/HDAC inhibitor), idasanutlin (MDM2-antagonist), cabazitaxel (microtubule inhibitor), filanesib (kinesin inhibitor), BIIB021 (HSPI), eribulin (microtubule inhibitor), and luminespib (HSPI). Interestingly, standard treatments in HB (carboplatin and doxorubicin) only demonstrated a minor effect. The screen revealed many new promising compounds for HB treatment. The efficacy of these agents should be confirmed in in vivo models in the future.