Targeting and Therapeutic Monitoring of H3K27M-Mutant Glioma

Abstract

Purpose of Review: H3K27M is a frequent histone mutation within diffuse midline gliomas and is associated with a dismal prognosis, so much so that the 2016 CNS WHO classification system created a specific category of "Diffuse Midline Glioma, H3K27M-mutant". Here we outline the latest pre-clinical data and ongoing current clinical trials that target H3K27M, as well as explore diagnosis and treatment monitoring by serial liquid biopsy. RecentFindings: Multiple epigenetic compounds have demonstrated efficacy and on-target effects in pre-clinical models. The imipridone ONC201 and the IDO1 inhibitor indoximod have demonstrated early clinical activity against H3K27M-mutant gliomas. Liquid biopsy of cerebrospinal fluid has shown promise for clinical use in H3K27M-mutant tumors for diagnosis and monitoring treatment response.Summary: While H3K27M has elicited a widespread platform of pre-clinical therapies with promise, much progress still needs to be made to improve outcomes for diffuse midline glioma patients. We present current treatment and monitoring techniques as well as novel approaches in identifying and targeting H3K27M-mutant gliomas.

Clinical Features and Molecular Markers on Diffuse Midline Gliomas With H3K27M Mutations: A 43 Cases Retrospective Cohort Study

“…Recently epigenetic studies have greatly broadened our understanding of its biological behavior and underlying mechanism. CSF analysis has also shown promise for the diagnosis and monitoring treatment response ( 23 ). In order to better understand and optimize survival in this unique and challenging patient population, further study is needed.…”

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

“…The H3 K27M mutation occurs in a unique spatiotemporal pattern, with midline gliomas involving the pons (i.e. DIPG) tending to occur in pediatric patients (<18 years of age), and midline gliomas involving the thalamus and spinal cord tending to occur in young adult patients [112] , [113] .…”

“…Standard therapy for midline gliomas involves neurosurgery, if feasible, followed by fractionated external beam radiotherapy. Radiotherapy remains the sole standard-of-care alone that is considered palliative, as relapse is inevitable and it only transiently improves symptoms and tumor burden and the 2-year survival rate in some forms of this disease is <10% [112] , [113] .…”

Radiosensitization in Pediatric High-Grade Glioma: Targets, Resistance and Developments

“…pHGG comprise all pediatric glioma lesions that are classified as ‘grade III’ or ‘grade IV’ by the World Health Organization (WHO) ( 6 ). A subset of pHGG, referred to as diffuse midline glioma (DMG) (formerly known as diffuse intrinsic pontine glioma or DIPG), arise in the midline of the brain and carry a particularly grim prognosis ( 5 , 7 ). Children with DMG have a median survival of 11 months, with less than 1 percent surviving past 5 years after diagnosis ( 8 , 9 ).…”

“…Gross total resection of diffuse tumors in the midline of the brain is particularly not possible as these tumors are intricately woven into areas of normal neural tissue that control vital functions, such as heart rate and breathing. The standard of care for most midline tumors, except for infants, is fractionated radiation therapy (RT) ( 7 ). Although this treatment modality provides temporary symptom relief, a minor delay in tumor progression, and a three-month survival benefit on average, it offers no chance for a cure ( 3 , 16 , 17 ).…”