Precision Medicine Approach for Children with Diffuse Intrinsic Pontine Glioma
OBJECTIVE: Children with diffuse intrinsic pontine glioma (DIPG) continue to have a dismal prognosis. Within the context of a multi-center trial, we evaluated whether genomic profiling, defined as sequencing of tumor and germline exomes and tumor RNA, can be used to identify distinct, actionable events leading to a personalized treatment plan. METHODS: Patients with newly diagnosed DIPG were eligible. Up to 7 biopsies were obtained at initial diagnosis. If sufficient tissue was available, xenograft development and cell culture expansion were attempted. Identified alterations were matched to therapeutic options using a custom drug-matching pipeline utilizing FDA-approved drugs, and potential repositioned agents. A multidisciplinary tumor board reviewed this data and generated a personalized treatment recommendation with up to four FDA approved agents for each patient. Patients who followed the therapy recommendation following focal radiotherapy were monitored for toxicity as well as clinical outcome. RESULTS: Whole exome and RNA sequencing was successfully completed and a treatment plan generated within 21 business days from tissue collection for all subjects (n = 15). The average mapped coverage was >400X across all tumor exomes (>200X across all normals) and we generated >128M mapped reads for each tumor RNA. Alterations in genes previously implicated in pediatric glioma were identified, including mutations in histone H3 (H3F3A), PDGFRA, TP53, KIT, KDR, ATRX, MET, IGFR1, BRAF, and PTEN, amongst others. Xenograft development and ctDNA collection are ongoing. CONCLUSION: It is feasible to apply comprehensive profiling to DIPG biopsies and to determine a therapy plan based on the specific alterations within each tumor.