Metabolic Features of Neurofibromatosis Type 1-Associated Tumors

Masgras, Ionica; Rasola, Andrea

doi:10.5772/intechopen.98661

Cited by 2 publications

(1 citation statement)

References 64 publications

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“…Observations indicate that affected individuals tend to present with deviations in their metabolic profiles, which may contribute to their smaller size and stature. Additional studies have revealed a lower prevalence of diabetes mellitus (mainly type 2) among NF1 patients, suggesting a complex interplay with signals and molecular pathways involved in glucose homeostasis and insulin signaling [151]. In fact, reduced thalamic glucose metabolism could be related to cognitive impairments [152].…”

Section: Stature and Metabolic Homeostasis Dysregulationmentioning

confidence: 99%

Drosophila Contributions towards Understanding Neurofibromatosis 1

Atsoniou,

Giannopoulou,

Georganta

et al. 2024

Cells

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Neurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the characteristic benign tumors known as neurofibromas, intense freckling and skin discoloration, and cognitive deficits, which characterize most children with the condition. Attention deficits and Autism Spectrum manifestations augment the compromised learning presented by most patients, leading to behavioral problems and school failure, while fragmented sleep contributes to chronic fatigue and poor quality of life. Neurofibromin (Nf1) is present ubiquitously during human development and postnatally in most neuronal, oligodendrocyte, and Schwann cells. Evidence largely from animal models including Drosophila suggests that the symptomatic variability may reflect distinct cell-type-specific functions of the protein, which emerge upon its loss, or mutations affecting the different functional domains of the protein. This review summarizes the contributions of Drosophila in modeling multiple NF1 manifestations, addressing hypotheses regarding the cell-type-specific functions of the protein and exploring the molecular pathways affected upon loss of the highly conserved fly homolog dNf1. Collectively, work in this model not only has efficiently and expediently modelled multiple aspects of the condition and increased understanding of its behavioral manifestations, but also has led to pharmaceutical strategies towards their amelioration.

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Section: Stature and Metabolic Homeostasis Dysregulationmentioning

confidence: 99%

Drosophila Contributions towards Understanding Neurofibromatosis 1

Atsoniou,

Giannopoulou,

Georganta

et al. 2024

Cells

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High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency

Dubey,

Rai,

Guillen

et al. 2024

Preprint

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Neurofibromatosis type 1 (NF1)-associated high-grade gliomas (HGGs) harboring ATRX mutations exhibit an aggressive clinical phenotype, driven by heightened genomic instability and metabolic reprogramming. Existing therapies, including chemotherapy and radiotherapy, are limited by resistance mechanisms and formation of secondary malignancy, underscoring the need for novel therapeutic strategies. Here, we report the results of a high-throughput screening of 10,000 small molecules aimed at identifying compounds selectively targeting vulnerabilities associated with concurrent ATRX and NF1 loss. Among the screened compounds, K784-6195 (ChemDiv ID) emerged as a promising candidate, exhibiting marked selective cytotoxicity in NF1-associated glioma cell lines with ATRX deficiency (IC50 = 4.84 µM). In comparison, wild-type ATRX sporadic glioma cell lines (U251) exhibited significantly reduced sensitivity to K784-6195 (IC50 = 37.03 µM). However, ATRX knockout U251 glioma cells recapitulating concurrent ATRX and NF1 loss exhibited heightened susceptibility to K784-6195 (IC50 = 20-23 µM) compared to their wild-type counterpart. Metabolomic analysis revealed that K784-6195 treatment impairs metabolic pathways, including the pentose phosphate pathway, glutamine metabolism, and redox homeostasis, leading to oxidative stress and impaired cell survival. These findings highlight K784-6195 as a promising candidate for therapeutic development, offering a targeted approach for the treatment of NF-1 associated HGGs with ATRX deficiency.

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Metabolic Features of Neurofibromatosis Type 1-Associated Tumors

Cited by 2 publications

References 64 publications

Drosophila Contributions towards Understanding Neurofibromatosis 1

Drosophila Contributions towards Understanding Neurofibromatosis 1

High-Throughput Targeted Drug Screening for NF1-associated High-Grade Gliomas with ATRX Deficiency

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