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

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.

High-Throughput Global Phosphoproteomic Profiling Using Phospho Heavy-Labeled-Spiketide FAIMS Stepped-CV DDA (pHASED)

“…Proteomics and phosphoproteomics have been acknowledged as being among the most effective strategies to predict drug sensitivities (1, 51). However, we are yet to establish phosphoproteomic profiling in the clinical setting, or even to provide such as an additive resource to genomically predicted therapeutic strategies; the establishment of which would represent a pivotal advance in precision-medicine treatment regimens.…”

“…Mass spectrometry approaches for global high-throughput quantitation of cellular phosphoproteomes have been increasingly applied to cancer specimens as they provide powerful tools for the identification of signaling pathways including kinases, phosphatases and cell cycle regulators that drive disease initiation and progression (1–3). Deregulation of kinase and phosphatase activity plays a critical role in cancer development and relapse (4–7), highlighting kinases as important therapeutic targets in the clinic (8, 9).…”

Preclinical and clinical evaluation of German-sourced ONC201 for the treatment of H3K27M-mutant diffuse intrinsic pontine glioma

“…These complementary effects highlight the therapeutic potential of ONC201 in vivo . 41 ONC201 and GsONC201 both modulated mitochondrial function, specifically in DIPG tissues, and potentially decreased global dopamine signaling ( Figure 3Ci ), to significantly extend the survival of DIPG PDX models, albeit temporarily ( Figure 3D ). Recent studies show DIPG patients with increased 18 F-DOPA uptake during MRI, presented a median OS of ≤12 months, and a lower degree of tumor volume reduction following radiotherapy ( P = .001), independently correlating 18 F-DOPA uptake with OS.…”

“… 42 Therefore, in vivo DRD2 antagonism both in the tumor and normal tissues ( Figure 3Ci ) highlights the endogenous and exogenous contributions to the growth and survival of DIPG that we are only beginning to understand. 41 …”

The Intricate Epigenetic and Transcriptional Alterations in Pediatric High-Grade Gliomas: Targeting the Crosstalk as the Oncogenic Achilles’ Heel

“…Conversely, it exhibits no clinical benefit for pediatric DMGs [ 137 , 138 , 139 ]. As previously suggested by Filbin and Monje [ 20 ], the unique features of pHGGs cells could be particularly permissive to certain treatments, which are under exploration (for detailed review on current clinical trials involving the use of targeted therapies for pHGGs, see Findlay et al [ 140 ]). A first promising way towards innovative therapies is the use of histone deacetylase (HDAC) inhibitors such as panobinostat, showing preclinical activity against DMG H3K27-altered cells in vitro and in vivo on patient-derived xenograft models [ 141 , 142 , 143 ].…”