Pediatric brain tumors: the era of molecular diagnostics, targeted and immune-based therapeutics, and a focus on long term neurologic sequelae

Abstract

Pediatric brain tumors are the second most common malignancy of childhood after acute leukemia and the number one cause of cancer-related mortality1. Over the past decade, advanced molecular diagnostics have led to the discovery of new molecularly-defined tumor types with prognostic and therapeutic implications. Methylation profiles, whole genome sequencing, and transcriptomics have defined subgroups and revealed heterogeneity within commonly defined tumor entities2,3. These findings have also revealed important differences between adult and pediatric brain tumors of similar histology. The majority of pediatric low grade gliomas (pLGG) are defined by alterations in the mitogen-activated protein kinase (MAPK) pathway including BRAFV600E point mutation, K1AA1549-BRAF fusion, and FGFR1 alterations as opposed to IDH1/2 mutations and 1p/19q co-deletion seen more frequently in adult low grade gliomas4. These findings have led to targeted therapies, namely BRAF and MEK inhibitors, which are currently being evaluated in phase III clinical trials and may soon supplant chemotherapy as standard of care for pLGG's. While targeted therapy trials for pediatric brain tumors have had significant success, immunotherapy remains a challenge in a group of tumors with generally lower mutational burden compared to adult tumors and relatively “cold” immune microenvironment. Despite this, a wide array of immunotherapy trials including vaccine therapies, immune checkpoint blockade, chimeric antigen receptor (CAR) T cells, and viral therapies are on-going. Unique to pediatrics, multiple clinical trials have sought to answer the question of whether the most malignant pediatric brain tumors in the youngest patients can be successfully treated with high dose chemotherapy in lieu of radiation to avoid devastating long-term neurocognitive deficits. Due to the collaborative work of multiple pediatric neuro-oncology consortiums, the recent history of pediatric brain tumor research is one of efficient translation from bench to bedside in a rare group of tumors resulting in significant progress in the field. Here, advances in the areas of molecular characterization, targeted and immune-based therapies, and reduction in long term co-morbidities will be reviewed.