Advances in Targeted Therapies for Pediatric Brain Tumors

Abstract

Purpose of Review Over the last years, our understanding of the molecular biology of pediatric brain tumors has vastly improved. This has led to more narrowly defined subgroups of these tumors and has created new potential targets for molecularly driven therapies. This review presents an overview of the latest advances and challenges of implementing targeted therapies into the clinical management of pediatric brain tumors, with a focus on gliomas, craniopharyngiomas, and medulloblastomas. Recent Findings Pediatric low-grade gliomas (pLGG) show generally a low mutational burden with the mitogen-activated protein kinase (MAPK) signaling presenting a key driver for these tumors. Direct inhibition of this pathway through BRAF and/or MEK inhibitors has proven to be a clinically relevant strategy. More recently, MEK and IL-6 receptor inhibitors have started to be evaluated in the treatment for craniopharyngiomas. Aside these low-grade tumors, pediatric high-grade gliomas (pHGG) and medulloblastomas exhibit substantially greater molecular heterogeneity with various and sometimes unknown tumor driver alterations. The clinical benefit of different targeted therapy approaches to interfere with altered signaling pathways and restore epigenetic dysregulation is undergoing active clinical testing. For these multiple pathway-driven tumors, combination strategies will most likely be required to achieve clinical benefit. Summary The field of pediatric neuro-oncology made tremendous progress with regard to improved diagnosis setting the stage for precision medicine approaches over the last decades. The potential of targeted therapies has been clearly demonstrated for a subset of pediatric brain tumors. However, despite clear response rates, questions of sufficient blood-brain barrier penetration, optimal dosing, treatment duration as well as mechanisms of resistance and how these can be overcome with potential combination strategies need to be addressed in future investigations. Along this line, it is critical for future trials to define appropriate endpoints to assess therapy responses as well as short and long-term toxicities in the growing and developing child.

Radiation in Combination With Targeted Agents and Immunotherapies for Pediatric Central Nervous System Tumors - Progress, Opportunities, and Challenges

“…Prospective studies are underway to evaluate if infantile HGG with such fusion events demonstrate durable response to TKI and if this treatment strategy can be applied to older patients with RTK fusions (NCT04655404, NCT03213704, NCT02576431, NCT02650401). Unfortunately, pHGG affecting older children, including histone mutant cases, are characterized by a combination of molecular alterations that increase the chances that one agent will fail due to resistance or inherent plasticity in oncogenic pathways driving tumor growth ( 20 , 28 , 29 ). In such cases, combinations of drugs and/or radiation offer the potential of increasing therapeutic response and reducing risk of resistance.…”

DNA methylation-based classification of malformations of cortical development in the human brain

“…DNA methylation analysis already fosters detection and molecular characterization of more specific and new disease entities in the broad group of brain tumors, particularly those characterized by specific pathogenic variants or treatable by targeted therapies [ 28 , 34 , 41 , 51 , 64 , 68 ]. We assume that the disease classification of MCD will also show such a dynamic adaptation, with more molecular genetic data becoming available over time.…”

Facing CAR T Cell Challenges on the Deadliest Paediatric Brain Tumours

“…Group 4 is the least understood group but the most prevalent. This group represents 35% of all MBs, with a 5-year OS of 75–90% [ 8 , 40 ]. Multiple histone mutations and epigenetic aberrations have been found in this subtype.…”

“…pHGGs present with extensive tumour heterogeneity. Although different pHGG subgroups have been proposed in terms of anatomical location, clinical outcome, histone mutations, or pathway alterations, their great heterogeneity complicates their classification and treatment [ 8 , 43 , 44 , 45 , 46 ]. In addition, the molecular genetics of pHGGs differ between infant and older children with HGG [ 47 , 48 ].…”

“…Advances in molecular characterisation in the last years have brought the identification of new potential targeted molecular therapies that are being tested in early-phase clinical trials [ 5 , 8 ].…”