Abstract
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor with a peak incidence in middle childhood and a median survival of less than 1 year. The dismal prognosis associated with DIPG has been exacerbated by the failure of over 250 clinical trials to meaningfully improve survival compared with radiotherapy, the current standard of care. The traditional practice to not biopsy DIPG led to a scarcity in available tissue samples for laboratory analysis that till recently hindered therapeutic advances. Over the past few years, the acquisition of patient derived tumor samples through biopsy and autopsy protocols has led to distinct breakthroughs in the identification of key oncogenic drivers implicated in DIPG development. Aberrations have been discovered in critical genetic drivers including histone H3, ACVR1, TP53, PDGFRA, and Myc. Mutations, previously not identified in other malignancies, highlight DIPG as a distinct biological entity. Identification of novel markers has already greatly influenced the direction of preclinical investigations and offers the exciting possibility of establishing biologically targeted therapies. This review will outline the current knowledge of the genomic landscape related to DIPG, overview preclinical investigations, and reflect how biological advances have influenced the focus of clinical trials toward targeted therapies.
Highlights
Diffuse intrinsic pontine glioma (DIPG) is a pediatric brainstem glioma that originates in the ventral pons, accounts for 75–80% of brainstem tumors in children and has a peak incidence in middle childhood [1,2,3]
DIPG have been classified as grade II–IV gliomas, namely, diffuse astrocytoma, anaplastic astrocytoma, or glioblastoma (GBM) [4]
The lack of progress of over three decades of clinical trials means that DIPG remains an almost universally fatal pediatric tumor
Summary
Diffuse intrinsic pontine glioma (DIPG) is a pediatric brainstem glioma that originates in the ventral pons, accounts for 75–80% of brainstem tumors in children and has a peak incidence in middle childhood [1,2,3]. Understanding the mutational processes underlying DIPG is of vital importance to identifying critical oncogenic pathways and defining high-frequency mutations with potential therapeutic relevance [18]. This review will highlight the current state of knowledge of DIPG tumor biology and underlying genomic processes. It will subsequently outline how this understanding is beginning to guide research in both preclinical models and in clinical trials of novel targeted agents. Functional analysis has highlighted the role of H3K27M as contributing to abnormal cell-cycle control, inhibition of autophagy and potentially augmenting tumor resistance to radiotherapy [23]. The combination of H3K27M with additional mutational events, such as altered cell-cycle regulatory
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
