Abstract B37: Chemi-genomic analysis of patient-derived xenografts to identify personalized therapies for medulloblastoma
Authors: Rusert Jessica M. , Garancher Alexandra , Udaka Yoko T. , Brabetz Sebastian , Esparza Lourdes A. , Seker-Cin Huriye , Qi Lin , Kogiso Mari , Schubert Simone , Milde Till , Cho Yoon-Jae , Li Xiao-Nan , Olson James M. , Crawford John R. , Levy Michael L. , Kool Marcel , Pfister Stefan M. , Wechsler-Reya Robert J. 
Published: March 2017

Medulloblastoma (MB) is the most common malignant brain tumor in children. Even with an intensive regimen of surgery, radiation and chemotherapy, one-third of patients still die from their disease. Moreover, survivors suffer devastating side effects including cognitive deficits, endocrine disorders and an increased incidence of secondary cancers later in life. Thus, more effective and less toxic therapies are desperately needed. Recent genomic analyses have identified 4 major subgroups of MB—WNT, SHH, Group 3 and Group 4—that differ in terms of mutations, gene expression profiles and patient outcomes. Despite this heterogeneity, all MB patients currently receive the same therapy. To identify novel therapies for each subgroup of MB, we have assembled a diverse panel of patient-derived xenograft (PDX) lines. These lines, established by orthotopic transplantation of tumor cells obtained from surgery, recapitulate the properties of patients' tumors more accurately than cultured cell lines. We are using these PDX lines to screen small molecule libraries and identify compounds that can inhibit tumor growth and survival. To date we have completed screening of 18 lines, including 10 representing Group 3 MB, the most aggressive and lethal form of the disease. Among the ~7800 compounds tested, we have found 20 that are effective against the majority of Group 3 PDX lines. Ongoing studies are focused on validating the activity of these compounds against additional Group 3 lines and moving the most promising ones forward into in vivo efficacy studies. Similar approaches will be pursued for each of the other subgroups of MB. Drug response data will also be compared with genomic and epigenomic data (whole exome and low coverage whole genome DNA sequencing, DNA methylation analysis, and gene expression profiling) to identify biomarkers of drug responsiveness and key pathways that may be exploited for therapy. Based on these studies, we hope to move away from a one-size-fits-all approach, and begin to treat each patient with therapies that are likely to be effective against their tumor.

Citation Format: Jessica M. Rusert, Alexandra Garancher, Yoko T. Udaka, Sebastian Brabetz, Lourdes A. Esparza, Huriye Seker-Cin, Lin Qi, Mari Kogiso, Simone Schubert, Till Milde, Yoon-Jae Cho, Xiao-Nan Li, James M. Olson, John R. Crawford, Michael L. Levy, Marcel Kool, Stefan M. Pfister, Robert J. Wechsler-Reya. Chemi-genomic analysis of patient-derived xenografts to identify personalized therapies for medulloblastoma. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B37.