Abstract 2797: Liver cancer patient-derived xenografts to improve disease management in childhood and adolescence: perspectives and challenges of personalized medicine. (2013)

Abstract Despite the rarity of each individual cancer type, about 200 different rare cancers constitute in total about 20% of all cancer cases, including pediatric cancers. In Europe, nearly half a million people live with a rare cancer. Like other rare diseases, rare cancers are particular challenging due to their low incidence, particularly for the identification of novel therapies that could improve patient survival. In spite of being the predominant type of pediatric liver malignances, hepatoblastoma (HB), with a world-wide incidence of 1 case per million persons per year, is a rare tumor. Differently from adult hepatocellular carcinoma (HCC) that develops on a cirrhotic or chronically-infected background, liver tumors in children and adolescents occur on apparently normal liver. The high rate (&gt; 60 %) of β-catenin activating mutations places HB as the human tumor most tightly associated with activation of the Wnt/β-catenin pathway. Evidence for (epi)genetic origin of HB is provided by its association with congenital anomalies, Beckwith-Wiedemann syndrome, and familial adenomatous polyposis, a disorder caused by germline mutation of APC, involved in β-catenin degradation. HCC, fibrolamellar carcinoma (FLC), and transitional liver cell tumors (TLCT), which combines histological features of HB and HCC, also arise in children and adolescents, at a lower extent though. Sporadically, very rare forms of liver tumor likely of non-epithelial origin such as rhabdoid tumor or hepatic sarcoma also occur. In order to assist medical decision on the management of liver cancer in childhood and adolescence, we have launched a program aimed at the constitution of liver cancer patient-derived xenografts (PDXs). At present, 8/24 HBs, 2/2 TLCTs, 0/2 FLCs, 1/1 rhabdoid tumor and 0/1 hepatic sarcoma have been successfully grown in immunocompromised mice. HB, TLCT and rhabdoid PDXs maintain the histological features of primary human tumors, and upon treatment with different chemotherapy agents, these models show unique profiles of response, indicating a tumor-specific sensitivity. Given the relatively high number of HB models obtained, HB PDXs could be used as a preclinical cohort for phase II-like studies. This would allow the pre-screen of therapeutic solutions that would require years when not decades to be put in place via standard clinical assays. Moreover, as several HB PDXs harbour activating mutation of β-catenin, they could serve as very powerful tools for the development of efficacious Wnt/β-catenin inhibitors. In addition, for sporadic liver tumors like TLCT and rhabdoid tumor, as the creation of a preclinical cohort is hard to propose, a comprehensive drug screening in vivo could orientate adjuvant therapy in view of a personalized treatment choice, or contribute to accumulate evidence on the usefulness of the tested drugs on such types of liver malignancies. Citation Format: Stefano Cairo, Aurore Gorse, Delphine Nicolle, Erwan Selingue, Frédéric Gauthier, Christophe Chardot, Elie Fadel, Dominique Elias, Daniel Orbach, Catherine Guettier, Arnaud Beurdeley, Vanessa Yvonnet, Olivier Deas, Monique Fabre, Laurence Brugières, Sophie Branchereau, Jean-Gabriel Judde. Liver cancer patient-derived xenografts to improve disease management in childhood and adolescence: perspectives and challenges of personalized medicine. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2797. doi:10.1158/1538-7445.AM2013-2797