Pediatric low-grade glioma: Targeted therapeutics and clinical trials in the molecular era

Manoharan, Neevika; Liu, Kevin X.; Mueller, Sabine; Haas‐Kogan, Daphne A.; Bandopadhayay, Pratiti

doi:10.1016/j.neo.2022.100857

Cited by 34 publications

(23 citation statements)

References 80 publications

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“…For low-grade, well-circumscribed tumors, total resection in combination with radiotherapy, is associated with better overall survival (OS) and excellent progression-free survival (PFS) [140]. Maximal surgical resection, followed by radiotherapy plus concomitant and maintenance chemotherapy with temozolomide (TMZ), is more indicated for high-grade gliomas such as GBMs and MBs, although almost all patients experience tumor progression and worst OS [141,142].…”

Section: Central Nervous System Tumoursmentioning

confidence: 99%

Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors

Buccarelli,

Castellani,

Fiorentino

et al. 2024

Cells

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Transglutaminase type 2 (TG2) is the most ubiquitously expressed member of the transglutaminase family. TG2 catalyzes the transamidation reaction leading to several protein post-translational modifications and it is also implicated in signal transduction thanks to its GTP binding/hydrolyzing activity. In the nervous system, TG2 regulates multiple physiological processes, such as development, neuronal cell death and differentiation, and synaptic plasticity. Given its different enzymatic activities, aberrant expression or activity of TG2 can contribute to tumorigenesis, including in peripheral and central nervous system tumors. Indeed, TG2 dysregulation has been reported in meningiomas, medulloblastomas, neuroblastomas, glioblastomas, and other adult-type diffuse gliomas. The aim of this review is to provide an overview of the biological and functional relevance of TG2 in the pathogenesis of nervous system tumors, highlighting its involvement in survival, tumor inflammation, differentiation, and in the resistance to standard therapies.

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Section: Central Nervous System Tumoursmentioning

confidence: 99%

Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors

Buccarelli,

Castellani,

Fiorentino

et al. 2024

Cells

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“…pLGGs are among the most common childhood brain tumors, representing approximately 30% of brain tumors in 0–19 year olds, and while treatments are available, they can come at a high cost [1]. Like pHGGs, pLGGs have distinct anatomical and age-dependent patterns and are often driven by alterations or fusions in single genes that impact the MAPK pathway or MYB gene family, which distinguishes them from adult LGGs [3, 39, 40]. Tumors in this category include WHO grade 1 tumors: pilocytic astrocytoma, which can be either sporadic or neurofibromatosis 1 (NF1) associated, optic tumors, ganglioglioma, and dysembryoplastic neuroepithelial tumor, and WHO grade 2 tumors: diffuse astrocytoma, pleomorphic xanthoastrocytoma, and oligodendroglioma.…”

Section: Overview Of Pediatric Gliomasmentioning

confidence: 99%

Pediatric Glioma Models Provide Insights into Tumor Development and Future Therapeutic Strategies

Foss¹,

Pathania²

2023

Dev Neurosci

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In depth study of pediatric gliomas has been hampered due to difficulties in accessing patient tissue and a lack of clinically representative tumor models. Over the last decade, however, profiling of carefully curated cohorts of pediatric tumors has identified genetic drivers that molecularly segregate pediatric gliomas from adult gliomas. This information has inspired the development of a new set of powerful in vitro and in vivo tumor models that can aid in identifying pediatric-specific oncogenic mechanisms and tumor microenvironment interactions. Single-cell analyses of both human tumors and these newly developed models have revealed that pediatric gliomas arise from spatiotemporally discrete neural progenitor populations in which developmental programs have become dysregulated. Pediatric high-grade gliomas also harbor distinct sets of co-segregating genetic and epigenetic alterations, often accompanied by unique features within the tumor microenvironment. The development of these novel tools and data resources has led to insights into the biology and heterogeneity of these tumors, including identification of distinctive sets of driver mutations, developmentally restricted cells of origin, recognizable patterns of tumor progression, characteristic immune environments, and tumor hijacking of normal microenvironmental and neural programs. As concerted efforts have broadened our understanding of these tumors, new therapeutic vulnerabilities have been identified, and for the first time, promising new strategies are being evaluated in the preclinical and clinical settings. Even so, dedicated and sustained collaborative efforts are necessary to refine our knowledge and bring these new strategies into general clinical use. In this review, we will discuss the range of currently available glioma models, the way in which they have each contributed to recent developments in the field, their benefits and drawbacks for addressing specific research questions, and their future utility in advancing biological understanding and treatment of pediatric glioma.

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“…The potential of molecularly targeted therapeutics to transform pLGG treatment is increasingly recognized, as evidenced by the FDA approval and ongoing clinical trials of RAF and MEK inhibitors 4,5 . Nonetheless, a thorough understanding of the biological and molecular foundations of pLGG tumors, beyond merely identifying specific markers such as BRAF alterations, is crucial to the success of targeted treatments.…”

Section: Introductionmentioning

confidence: 99%

Multiparametric MRI Along with Machine Learning Informs on Molecular Underpinnings, Prognosis, and Treatment Response in Pediatric Low-Grade Glioma

Kazerooni,

Kraya,

Rathi

et al. 2024

Preprint

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In this study, we present a comprehensive radiogenomic analysis of pediatric low-grade gliomas (pLGGs), combining treatment-naive multiparametric MRI and RNA sequencing. We identified three immunological clusters using XCell enrichment scores, highlighting an 'immune-hot' group correlating with poorer prognosis, suggesting potential benefits from immunotherapies. A radiomic signature predicting immunological profiles showed balanced accuracies of 81.5% and 84.4% across discovery and replication cohorts, respectively. Our clinicoradiomic model predicted progression-free survival with concordance indices of 0.71 and 0.77 in these cohorts, and the clinicoradiomic scores correlated with treatment response (p = 0.001). We also explored germline variants and transcriptomic pathways related to clinicoradiomic risk, identifying those involved in tumor growth and immune responses. This is the first radiogenomic analysis in pLGGs that enhances prognostication by prediction of immunological profiles, assessment of patients' risk of progression, prediction of treatment response to standard-of-care therapies, and early stratification of patients to identify potential candidates for novel therapies targeting specific pathways.

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Pediatric low-grade glioma: Targeted therapeutics and clinical trials in the molecular era

Cited by 34 publications

References 80 publications

Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors

Biological Implications and Functional Significance of Transglutaminase Type 2 in Nervous System Tumors

Pediatric Glioma Models Provide Insights into Tumor Development and Future Therapeutic Strategies

Multiparametric MRI Along with Machine Learning Informs on Molecular Underpinnings, Prognosis, and Treatment Response in Pediatric Low-Grade Glioma

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