New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma

Argersinger, Davis P.; Rivas, Sarah; Shah, Ashish H.; Jackson, Sadhana; Heiss, John D.

doi:10.3390/cancers13215280

Cited by 38 publications

(46 citation statements)

References 89 publications

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“…In general our results are consistent with frequencies of clinically significant mutations in DIPG reported in previous studies (Argersinger, et al, 2021; Buczkowicz and Hawkins, 2015).…”

Section: Resultssupporting

confidence: 93%

A disease model for Diffuse Intrinsic Pontine Glioma (DIPG) with mutations in TP53 and its application for drug repurposing

Yuryev

Nesterova

Sozin

et al. 2022

Preprint

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Brain cancers are ones of most aggressive and difficult to treat cancers. Despite numerous studies of the cellular mechanisms of gliomas, it is difficult to stop tumor growth. A complex genetic and epigenetic nature of many gliomas and poorly known pathways of human neuron precursors maturation suggest turning to big data analysis to find new insights and directions for drug development. We developed in silico molecular models and predicted molecular switches in signaling cascades that maintain multipotency of neuronal precursor cells in diffuse intrinsic pontine glioma (DIPG) driven by the H3K27M mutation and mutations in the TP53 gene. Oncogenes and biomarkers were predicted based on transcriptomics and mutational genomics data from a cohort of 30 patients with DIPG analyzed using Elsevier artificial intelligence methods and a collection of manually curated cancer hallmark pathways. The molecular models of DIPG with mutations in TP53 and histone 3 gene describe the mechanism of oligodendrocyte dedifferentiation due to activation of transcriptional factors OLIG2, SOX2, and POU5F1, epithelial-to-mesenchymal transition via strong EGFR and TGFR signaling, enhanced cell response to hypoxia via HIF1A signaling and enhanced angiogenesis by VEGFA overexpression. Using in silico analysis, we identified drugs capable of inhibiting mutant TP53: vorinostat, cisplatin, paclitaxel, and statins were top-ranked drugs. The predicted drugs and oncogenes had individual patient-level differences that can be visualized with created DIPG model and may be useful for future research in the field of personalized medicine.

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“…In general our results are consistent with frequencies of clinically significant mutations in DIPG reported in previous studies (Argersinger, et al, 2021; Buczkowicz and Hawkins, 2015).…”

Section: Resultssupporting

confidence: 93%

A disease model for Diffuse Intrinsic Pontine Glioma (DIPG) with mutations in TP53 and its application for drug repurposing

Yuryev

Nesterova

Sozin

et al. 2022

Preprint

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“…The common pathways that are affected in pediatric gliomas are cell proliferation, mitosis, and neo angiogenesis pathways, such as MAPK, EGFR, and VEGF pathways. The most common altered genes in pediatric gliomas are BRAF, TP53 , histone H3, FGFR , and MYB/MYBL1 [31] , [32] , [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] , [41] , [42] .…”

Section: Modeling Pediatric Gliomasmentioning

confidence: 99%

Pioneering models of pediatric brain tumors

Grigore¹,

Yang²,

Chen³

et al. 2023

Neoplasia

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“…Most commonly, a missense mutation change a lysine to methionine residue (K27M) in the histone H3 variants H3.3 or H3.1, resulting in a change in genetic expression that is believed to drive tumor formation and growth ( 87 , 90 ). These gliomas are also associated with a loss of trimethylation in residual H3K27 and an increase in H3K27 acetylation, thereby upregulating expression of proto-oncogenes and suppressing cellular differentiation ( 90 , 91 ).…”

Section: Molecular Landscapementioning

confidence: 99%

Surgical approaches to intramedullary spinal cord astrocytomas in the age of genomics

2022

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Intramedullary astrocytomas represent approximately 30%–40% of all intramedullary tumors and are the most common intramedullary tumor in children. Surgical resection is considered the mainstay of treatment in symptomatic patients with neurological deficits. Gross total resection (GTR) can be difficult to achieve as astrocytomas frequently present as diffuse lesions that infiltrate the cord. Therefore, GTR carries a substantial risk of new post-operative deficits. Consequently, subtotal resection and biopsy are often the only surgical options attempted. A midline or paramedian sulcal myelotomy is frequently used for surgical resection, although a dorsal root entry zone myelotomy can be used for lateral tumors. Intra-operative neuromonitoring using D-wave integrity, somatosensory, and motor evoked potentials is critical to facilitating a safe resection. Adjuvant radiation and chemotherapy, such as temozolomide, are often administered for high-grade recurrent or progressive lesions; however, consensus is lacking on their efficacy. Biopsied tumors can be analyzed for molecular markers that inform clinicians about the tumor’s prognosis and response to conventional as well as targeted therapeutic treatments. Stratification of intramedullary tumors is increasingly based on molecular features and mutational status. The landscape of genetic and epigenetic mutations in intramedullary astrocytomas is not equivalent to their intracranial counterparts, with important difference in frequency and type of mutations. Therefore, dedicated attention is needed to cohorts of patients with intramedullary tumors. Targeted therapeutic agents can be designed and administered to patients based on their mutational status, which may be used in coordination with traditional surgical resection to improve overall survival and functional status.

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New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma

Cited by 38 publications

References 89 publications

A disease model for Diffuse Intrinsic Pontine Glioma (DIPG) with mutations in TP53 and its application for drug repurposing

A disease model for Diffuse Intrinsic Pontine Glioma (DIPG) with mutations in TP53 and its application for drug repurposing

Pioneering models of pediatric brain tumors

Surgical approaches to intramedullary spinal cord astrocytomas in the age of genomics

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