Abstract 3107: A scientific task force to generate proof-of-concept data packages for clinical trials in pediatric cancers: The hepatoblastoma example

Abstract

Abstract Identification of new treatments for relapsing pediatric cancer is an unmet clinical need and a societal challenge. Hepatoblastoma (HB) is a rare tumor that constitutes the most frequent form of childhood liver cancer. Current improvement in medical care allows 80% of children to survive this disease, but no second line treatment is available at relapse, so that 20% will not survive. Patient population small size and very low mutation rate besides beta-catenin activating mutation, which is at present undruggable, make HB an orphan disease. Very few anti-cancer drugs evaluated for adult diseases are investigated in the pediatric population, with 12 drugs approved for adult cancers every year against 6 drugs approved in childhood cancer since 1978. The need of incentives to encourage pharmaceutical industry to invest in this field has been well received by the European and US medicine agencies, and recent modification to regulations on adult and pediatric oncology drug development are expected to induce pharmaceutical companies to test their new compounds in the pediatric setting. Parallel to this initiative, it is imperative that the scientific community develops research tools and scientific rational to assist drug development as well as repositioning of drugs already approved in adult cancers. To this aim, in collaboration with the International Childhood Liver Tumour Strategy Group (SIOPEL) and the network of hospitals in the Paris area (AP-HP), XenTech has launched in 2010 the development of a panel of HB patient-derived xenografts (HB-PDXs). To date, 26 HB-PDXs have been established from 80 engraftments from patients at surgery after chemotherapy or at relapse. As these models were established from tumor cells that either evaded chemotherapy or promoted local and distant metastases, they present a biological surrogate of the recurrent disease. From these PDXs, 9 cellular models have been established to allow the exploration of the functional mechanisms of tumor growth and resistance to treatment, as well as to facilitate drug screening. This project is receiving worldwide participation from the HB scientific community including clinicians, academic researchers and parents associations. Thanks to this joint effort all the models are now fully characterized at the molecular level, PDXs pharmacological profiling has been done and is currently ongoing for many of these models, and PDXs and cellular models are being used from a growing number of collaborators to perform 3D culture, to improve our knowledge on the HB biology and to identify new drugs. The ambition of this project is to generate a reference preclinical platform that will be used for research purposes by the academic community and as a testing site for biotechs and pharmaceutical companies to accelerate the identification of anti-cancer therapies for children with aggressive HB. Citation Format: Carolina Armengol, Roland Kappler, Liqin Zhu, Nikolai Timchenko, Dina Kats, Charles Keller, Lisa Howard, Christophe Grosset, Delphine Nicolle, Olivier Déas, Martina Pigazzi, Laurence Brugières, Charlotte Mussini, Louise Galmiche-Rolland, Christophe Chardot, Sophie Brancereau, Jean-Gabriel Judde, Stefano Cairo. A scientific task force to generate proof-of-concept data packages for clinical trials in pediatric cancers: The hepatoblastoma example [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3107.