Molecular profiling and targeted therapy in pediatric gliomas: review and consensus recommendations

Abstract

As the field of neuro-oncology makes headway in uncovering the key oncogenic drivers in pediatric glioma, the role of precision diagnostics and therapies continues to rapidly evolve with important implications for the standard of care for clinical management of these patients. Four studies at major academic centers were published in the last year outlining the clinically integrated molecular profiling and targeting of pediatric brain tumors; all 4 demonstrated the feasibility and utility of incorporating sequencing into the care of children with brain tumors, in particular for children and young adults with glioma. Based on synthesis of the data from these studies and others, we provide consensus recommendations for the integration of precision diagnostics and therapeutics into the practice of pediatric neuro-oncology. Our primary consensus recommendation is that next-generation sequencing should be routinely included in the workup of most pediatric gliomas.

Personalized Treatment of H3K27M-Mutant Pediatric Diffuse Gliomas Provides Improved Therapeutic Opportunities

“…Being controversially discussed some years ago, biopsy of DMGs has been shown to be safe, which we could also confirm in our case series (29,30). Hence, personalized treatment approaches based on comprehensive molecular profiling are considered a particularly promising treatment approach (27). In the underlying study, we investigated not only the presence of potential treatment targets but also clinical benefit via individualized treatment plans.…”

“…All patients responded to a combination with backbone treatment, which also included the case with the longest observed OS (44.5 months) in this cohort. Consequently, our data indicate that targeting molecular alterations of the PI3K/AKT/mTOR pathway in H3K27M glioma might represent a promising therapeutic approach worth validating in clinical trials that have already been initiated (27).…”

“…Personalization of therapy is of particular interest in poor prognosis tumors such as H3K27M glioma and in tumors where inconsistent gene alterations exist (27). As pediatric tumors harbor much less mutations than do adult cancers, precision targeted therapy is likely to be more effective against these tumors than standard population-based approaches (27,28). This has been corroborated by a recent prospective analysis confirming the presence of potentially targetable alterations in 76% of H3K27M-positive pontine gliomas (29).…”

“…Comprehensive dissection of the molecular signatures and specific targeting of these molecular driver signals is hoped to significantly improve mortality and morbidity of cancer patients (26). Personalization of therapy is of particular interest in poor prognosis tumors such as H3K27M glioma and in tumors where inconsistent gene alterations exist (27). As pediatric tumors harbor much less mutations than do adult cancers, precision targeted therapy is likely to be more effective against these tumors than standard population-based approaches (27,28).…”

Clinical efficacy and predictive biomarkers of ONC201 in H3 K27M-mutant diffuse midline glioma

“…The histone mutation H3 K27M in diffuse midline gliomas (DMG) is associated with aggressive clinical behavior and overall median survival of 12.0 months [1][2][3] . The H3 K27M mutation is most commonly found in midline central nervous system (CNS) structures in children and young adults 4 , where the thalamus and brainstem account for the majority of patients carrying the mutation 1,[5][6][7] . We assessed the bloodbrain barrier (BBB) penetration of ONC201 in midline brain structures in non-tumor bearing mice.…”