Abstract LB-041: Establishment and characterization of patient derived orthotopic xenograft mouse models representing a serial of primary and recurrent pediatric brain tumors
Authors: Du Yuchen , Kogiso Mari , Braun Frank , Qi Lin , Zhang Huiyuan , Lindsay Holly , Zhao Sibo , Injac Sarah , Cool Marcel , Stephan Clifford , Li Xiaonan 
Published: August 2018

BACKGROUD AND PURPOSE: Despite standard treatment largely benefits patients'survival, primary tumors may recur as aggressive, therapy resistant relapses. It is imperative to obtain a better understanding of the genetic and molecular changes that occur after primary tumor resection and treatment. To this end, we established a serial of PDOX models using patient tumor tissues procured at different times.

METHODS: Single cells were immediately dissociated from patient tumors procured from clinic, cultured in vitro and transplanted into mouse brains corresponding to the patient's tumor location. DNA and RNA were then extracted from patient and xenograft tumor tissues or cultured cells. Whole genome DNA methylation, transcriptomic profiling and RNA sequencing were performed. Immunohistological phenotypes were examined. Standard therapies which follow clinical regimen were conducted as well in tumor xenografts.

RESULTS: Currently, we successfully established three sets of matched primary and recurrent tumor xenografts (19850PNET, 100815GGG-GBM and 5958MB). Tumor-take rate increased from 50-70% of primary tumors to 100% of recurrent tumors with decreased tumor onset time (6 months to 3 months) that obtained usually after clinical treatment demonstrating progressive phenotypes. HE stainings from xenografts tumors recapitulated the very similar histological changes to patient counterparts. RNA sequencing reveals preserved and newly mutated genes in recurrent tumors compared to the primary ones. High-throughput drug screening using cultured patient tumor cells discovered a shared and a diverse panel of therapeutic targets that could be selected further for in vivo drug treatment in future. Three sets of tumor xenografts responded to standard therapy either the same or different from clinic outcome, which might indicate the intrinsic or inducible evolutional molecular changes during cancer progression and treatment at different stages. Molecular phenotypes such as genomic methylation and transcriptome profile are underway for these two sets of primary and recurrent tumors.

CONCLUSION: Three sets of matched primary and recurrent pediatric brain tumors, PNET/PNET, GGG/GBM and MB/MB, were successfully establised in pediatric orthotopic mice tumor models (PDOXs) providing clinically-relevant and biologically-accurate animal model systems for development of novel therapeutic targets. Responses of primary and recurrent tumor xenografts to standard chemo-therapy were different possibly due to evolutionarily molecular changes in recurrent tumors during progression or induced by therapies.

Citation Format: Yuchen Du, Mari Kogiso, Frank Braun, Lin Qi, Huiyuan Zhang, Holly Lindsay, Sibo Zhao, Sarah Injac, Marcel Cool, Clifford Stephan, Xiaonan Li. Establishment and characterization of patient derived orthotopic xenograft mouse models representing a serial of primary and recurrent pediatric brain tumors [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 LB-041.