Abstract 4628: Tailoring personalized strategies for children with treatment-refractory liver cancer
Authors: Cairo Stefano , Noblet Bénédicte , Rasmussen Samuel , Svalina Matthew N. , Mevel Katell , Ven Enora Le , Nicolle Delphine , Déas Olivier , Mussini Charlotte , Branchereau Sophie , Judde Jean-Gabriel , Keller Charles 
Published: August 2018

Abstract
Tumour heterogeneity is probably the reason for different sensitivity to the same treatment in patients. Therefore, we urgently need to develop tools to help assign the right treatment to the right patient. This is particularly challenging for paediatric cancers. Hepatoblastoma (HB) is the most frequent malignant embryonal tumor of the liver in childhood. About 25% of HB patients will develop metastatic disease which is associated with a poor prognosis. Because of the small number of patients eligible for enrollment, clinical trials in most of cases could not provide clinicians with statistically significant results. In oncology, preclinical data are generally poorly predictive of treatment efficacy in patients, probably due to oversimplification of tumor biology and underrepresentation of the genetic tumor heterogeneity observed in patients. To face this issue, we have launched a program to generate patient-derived xenografts, the gold standard in preclinical oncology, from surgical tissue from HB patients after chemotherapy, at relapse and from local and distant metastases. Therefore, the models developed are representative of relapsing, metastatic HB. So far, a panel of 24 HB PDXs models has been established. From these models 10 cell lines could be established so far to be used for large-scale in vitro screening of anticancer compound libraries. The aim of this project is to combine in vitro and in vivo drug screening to provide strong preclinical rationale to the development of novel therapeutic options for children with HB, and to identify candidate biomarkers predictive of tumor response. In vitro screening of a HB PDX-derived cells with a library of 60 compounds corresponding to treatments already available in the clinic lead us to identify 4 compounds with very strong cytotoxic activity on HB cells. One of them, Volasertib, a PLK1 inhibitor, was selected to be tested in the HB PDX the cells were derived from. The in vivo study compared the effect of volasertib as single agent or in combination with irinotecan to irinotecan alone or in combination with temozolomide. The results showed that high dose volasertib induce tumor regression with efficacy comparable to irinotecan/temozolomide combination. Following these encouraging results, Volasertib was tested in the complete panel of HB PDX-derived cells, and the majority of them showed strong sensitivity to the drug. This sensitivity was associated with specific molecular alterations that might be used as biomarkers to predict tumor sensitivity. Overall, these results suggest that volasertib could be an effective second line treatment for children with recurrent HB, and that this platform could be a very important preclinical tool to foster translational research in HB.
Citation Format: Stefano Cairo, Bénédicte Noblet, Samuel Rasmussen, Matthew N. Svalina, Katell Mevel, Enora Le Ven, Delphine Nicolle, Olivier Déas, Charlotte Mussini, Sophie Branchereau, Jean-Gabriel Judde, Charles Keller. Tailoring personalized strategies for children with treatment-refractory liver cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4628.