2021
DOI: 10.1038/s41388-021-02102-y
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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… Show more

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Cited by 56 publications
(57 citation statements)
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“…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.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…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.…”
Section: Discussionmentioning
confidence: 99%
“…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 (13). Deregulation of kinase and phosphatase activity plays a critical role in cancer development and relapse (47), highlighting kinases as important therapeutic targets in the clinic (8, 9).…”
Section: Introductionmentioning
confidence: 99%
“…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.…”
Section: Discussionmentioning
confidence: 99%
“… 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 …”
Section: Discussionmentioning
confidence: 99%
“…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 ].…”
Section: Targeting the Synergistic Epigenetic/transcriptional Oncogen...mentioning
confidence: 99%