Pharmaco-proteogenomic profiling of pediatric diffuse midline glioma to inform future treatment strategies


Nature
Matthew Dun.jpg
Dr. Matt Dun, Associate Professor, University of Newcastle

Dr. Dun’s latest research helps to outline key attributes between DIPG and DMGs and how we might best find complementary strategies to attack DMG to improve prognoses.  This, when combined with further genetic analysis, will lead to improved outcomes for children fighting these brain tumors.

Abstract

Diffuse midline glioma (DMG) is a deadly pediatric and adolescent central nervous system (CNS) tumor localized along the midline structures of the brain atop the spinal cord. With a median overall survival (OS) of just 9–11-months, DMG is characterized by global hypomethylation of histone H3 at lysine 27 (H3K27me3), driven by recurring somatic mutations in H3 genes including, HIST1H3B/C (H3.1K27M) or H3F3A (H3.3K27M), or through overexpression of EZHIP in patients harboring wildtype H3. The recent World Health Organization’s 5th Classification of CNS Tumors now designates DMG as, ‘H3 K27-altered’, suggesting that global H3K27me3 hypomethylation is a ubiquitous feature of DMG and drives devastating transcriptional programs for which there are no treatments. H3-alterations co-segregate with various other somatic driver mutations, highlighting the high-level of intertumoral heterogeneity of DMG. Furthermore, DMG is also characterized by very high-level intratumoral diversity with tumors harboring multiple subclones within each primary tumor. Each subclone contains their own combinations of driver and passenger lesions that continually evolve, making precision-based medicine challenging to successful execute. Whilst the intertumoral heterogeneity of DMG has been extensively investigated, this is yet to translate to an increase in patient survival. Conversely, our understanding of the non-genomic factors that drive the rapid growth and fatal nature of DMG, including endogenous and exogenous microenvironmental influences, neurological cues, and the posttranscriptional and posttranslational architecture of DMG remains enigmatic or at best, immature. However, these factors are likely to play a significant role in the complex biological sequelae that drives the disease. Here we summarize the heterogeneity of DMG and emphasize how analysis of the posttranslational architecture may improve treatment paradigms. We describe factors that contribute to treatment response and disease progression, as well as highlight the potential for pharmaco-proteogenomics (i.e., the integration of genomics, proteomics and pharmacology) in the management of this uniformly fatal cancer.

Conclusion

Despite extensive developments in novel targeted therapies and precision medicines, the prognosis and outcomes of patients diagnosed with DMG remain unacceptably poor. The recent 5th Edition of the WHO Classification of Tumors of the CNS, subtypes DMG based on H3 K27-alterations and facilitates the categorization of patients according to distinct clinicopathological and molecular features. It is important to note that the hallmark H3-alterations that give rise to DMG are somewhat unique to these tumors; therefore, novel modalities targeting these alterations herald our greatest chance to improve treatment. However, long-term successful outcomes will require treatments that take into appreciation the yet-to-be-characterized proteomic heterogeneity of DMG, including the assessment of the posttranslational architecture. Furthermore, future studies focused on regional contributions to tumor growth and survival are also needed as are studies to determine the mechanisms that influence immune system avoidance. Until genomics-based treatment target identification is integrated with pharmacogenomics and pharmacoproteomics research, the success of trials will remain low, with little hope of patients achieving long-term survival. Coupled evaluation of the DMG genome with the respective proteome, will enhance treatment selection/development, refine the evaluation of patient prognosis, and lead to the development, we hope, of approaches that improve outcomes for those diagnosed with the most aggressive, and poorly survived pediatric cancer.

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