Abstract Comprehensive molecular characterization of pediatric brain tumors has led to more refined diagnoses. However, the feasibility of performing multi-omic and functional precision medicine approaches using ex-vivo drug screening in the clinical setting was previously unknown. Patients with newly diagnosed or recurrent central nervous system tumors were enrolled in a feasibility study of multi-omic analysis including whole genome trio germline sequencing, tumor whole exome/RNA sequencing, RNA-based DiSCoVER analysis, methylation profiling, immunogenic potential analysis, and ex-vivo drug screening utilizing a customized panel of 175 FDA-approved/investigational drugs. Findings were presented at a multidisciplinary molecular neuro-oncology tumor board. Eighteen patients (9 female; average age 9.4 years; 12 newly diagnosed, 6 with recurrent disease; 5 high grade gliomas, 4 ependymomas, 4 embryonal tumors, 3 low grade gliomas, 2 others) were enrolled between 2020-2022. Whole genome germline testing (n = 18) was normal in half of patients (pathogenic germline mutations in 3 patients, variants of unknown significance in 6 patients). Ex-vivo drug screening results (n = 14) varied among patients, however sub-micromolar efficacy was commonly observed for proteasome inhibitors, HDAC inhibitors, and topoisomerase II inhibitors. Average time from surgery to receipt of finalized results varied across platforms but were overall under one month (drug screening 5.7 days, whole exome/RNA sequencing 14.8 days, whole genome germline 10.6 days, methylation 21 days). Fifteen patients had a modification in diagnosis and 4 patients had a change in tumor classification. Our results led to changes in management of 9 patients (6 based on molecular findings, 4 based on drug screening, 1 based on methylation, 2 based on RNA DiSCoVER Analysis). This study demonstrates the feasibility of timely ex-vivo drug screening and multi-omic analysis and show that these data may lead to changes in patient diagnosis/management. Importantly, our findings are the basis of an ongoing trial for recurrent medulloblastoma (NCT05057702).
Crawford et al. (Fri,) studied this question.