Recent Advances in Understanding the Role of Autophagy in Paediatric Brain Tumours

Autophagy is a degradative process occurring in eukaryotic cells to maintain homeostasis and cell survival. After stressful conditions including nutrient deprivation, hypoxia or drugs administration, autophagy is induced to counteract pathways that could lead to cell death. In cancer, autophagy plays a paradoxical role, acting both as tumour suppressor—by cleaning cells from damaged organelles and inhibiting inflammation or, alternatively, by promoting genomic stability and tumour adaptive response—or as a pro-survival mechanism to protect cells from stresses such as chemotherapy. Neural-derived paediatric solid tumours represent a variety of childhood cancers with unique anatomical location, cellular origins, and clinical presentation. These tumours are a leading cause of morbidity and mortality among children and new molecular diagnostics and therapies are necessary for longer survival and reduced morbidity. Here, we review advances in our understanding of how autophagy modulation exhibits antitumor properties in experimental models of paediatric brain tumours, i.e., medulloblastoma (MB), ependymoma (EPN), paediatric low-grade and high-grade gliomas (LGGs, HGGs), atypical teratoid/rhabdoid tumours (ATRTs), and retinoblastoma (RB). We also discuss clinical perspectives to consider how targeting autophagy may be relevant in these specific paediatric tumours.

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Multicentre study of perfusion magnetic resonance imaging in paediatric brain tumours

Neuro-Oncology ◽

10.1093/neuonc/noz167.041 ◽

2019 ◽

Vol 21 (Supplement_4) ◽

pp. iv10-iv10 ◽

Cited By ~ 1

Author(s):

Stephanie Withey ◽

Lesley MacPherson ◽

Adam Oates ◽

Stephen Powell ◽

Jan Novak ◽

...

Keyword(s):

Contrast Agent ◽

Brain Tumours ◽

Cerebral Blood Volume ◽

Perfusion Magnetic Resonance Imaging ◽

Low Grade ◽

Dynamic Susceptibility ◽

High Grade ◽

Dynamic Susceptibility Contrast ◽

Perfusion Studies ◽

Paediatric Brain Tumours

Abstract Studies in adults have shown that brain tumour perfusion correlates with grade. These studies are dominated by gliomas grade II to IV which are rare in children. The standard method, Dynamic Susceptibility Contrast MRI, provides estimates of relative cerebral blood volume (rCBV) but contrast agent leakage affects rCBV accuracy. The majority of perfusion studies have been conducted at single centres and variation in acquisition protocols makes the generalizability of results questionable. The aim of this study was to compare leakage-corrected rCBV with grade in paediatric brain tumours at multiple centres. Scans were analysed from 85 patients at 4 centres on 6 scanners prior to treatment. MRI protocols varied between centres. Histological diagnoses including grade were obtained. Whole-tumour median rCBV was significantly higher in the 45 high grade than the 40 low grade tumours (2.54 ± 1.63 ml/100ml vs 1.68 ± 1.36 ml/100ml, p=0.010). Low grade tumours, particularly pilocytic astrocytomas (grade I), displayed more contrast agent leakage consistent with their appearance on contrast enhanced images and required more leakage correction than high grade tumours. This finding differs from that in adults where contrast agent uptake is usually associated with higher grade. A cut-off of 1.70 ml/100ml for rCBV gave sensitivity and specificity of 76% and 65% respectively for discriminating grade. In summary, perfusion MRI can be used to help distinguish between low and high grade paediatric brain tumours. This finding is robust across multiple centres and acquisition protocols but correction should be made for leakage of contrast agent from the vessels.

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Prevention of radiotherapy-induced neurocognitive dysfunction in survivors of paediatric brain tumours: the potential role of modern imaging and radiotherapy techniques

The Lancet Oncology ◽

10.1016/s1470-2045(17)30030-x ◽

2017 ◽

Vol 18 (2) ◽

pp. e91-e100 ◽

Cited By ~ 18

Author(s):

Thankamma Ajithkumar ◽

Stephen Price ◽

Gail Horan ◽

Amos Burke ◽

Sarah Jefferies

Keyword(s):

Brain Tumours ◽

Potential Role ◽

Neurocognitive Dysfunction ◽

Modern Imaging ◽

Radiotherapy Techniques ◽

Paediatric Brain Tumours

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Peripheral Mechanisms of Symptom Generation in Irritable Bowel Syndrome

Canadian Journal of Gastroenterology ◽

10.1155/2001/690794 ◽

2001 ◽

Vol 15 (suppl b) ◽

pp. 14B-16B ◽

Cited By ~ 12

Author(s):

Stephen M Collins

Keyword(s):

Nervous System ◽

Irritable Bowel Syndrome ◽

Experimental Models ◽

Low Grade ◽

Sensory Physiology ◽

Somatic Pain ◽

Inflammatory Stimuli ◽

The Central Nervous System ◽

Irritable Bowel

There is considerable interest in the mechanisms that underlie symptom generation in irritable bowel syndrome (IBS) and particularly those mechanisms peripheral to higher centres in the nervous system. While the central nervous system is important in IBS, it is restricted largely to the role of behaviour in stress perception and symptom reporting. The gut and the autonomic nervous system are principal areas of research in identifying mechanisms underlying symptom generation and in the identification of new targets for drug development. While motility changes occur in IBS, they are neither specific nor predictable, and this is one reason why drugs aimed at influencing motility patterns have enjoyed limited success to date. This success has prompted interest in sensory physiology to explain pain and other discomforts expressed by patients with IBS. Patients with IBS exhibit intolerance to rectal distension and other manoeuvres of the gut, while exhibiting normal or raised thresholds for somatic pain. The mechanisms underlying the development of hyperalgesia or allodynia in the gut remain to be determined. In other systems and experimental models, low grade inflammation is a predicable inducer of these states, and recent evidence suggests that a subpopulation of patients with IBS develop chronic symptoms after acute gastroenteritis. This and other inflammatory stimuli may induce a hyperalgesic state and alter motor function in patients with IBS. Substances that mediate these changes are not fully understood, but there is growing recognition of the role of serotonin as a sensitizing agent.

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TBIO-14. CHARACTERISATION OF THE ARGININE PATHWAY ENZYMES IN PAEDIATRIC BRAIN TUMOURS TO DETERMINE SUSCEPTIBILITY TO THERAPEUTIC ARGININE DEPLETION

Neuro-Oncology ◽

10.1093/neuonc/noaa222.841 ◽

2020 ◽

Vol 22 (Supplement_3) ◽

pp. iii469-iii469

Author(s):

Eleanor Bishop ◽

Monika Dimitrova ◽

Lisa Storer ◽

Richard Grundy ◽

Madhumita Dandapani

Keyword(s):

Brain Tumours ◽

Urea Cycle ◽

High Grade Glioma ◽

Tissue Microarrays ◽

Low Grade ◽

Antibody Expression ◽

Immunohistochemical Methods ◽

Ornithine Transcarbamoylase ◽

Paediatric Brain Tumours ◽

Low Expression

Abstract INTRODUCTION Extracellular arginine dependency (auxotrophy) is increasingly being recognised in several tumours. This is due to the inability of cancer cells to recycle or synthesise intracellular arginine through the urea cycle pathway compared to normal cells. Whilst adult glioblastoma is known to exhibit this, the expression of the arginine pathway enzymes has not been delineated in paediatric brain tumours. METHODS We used immunohistochemical methods to stain for arginine pathway enzymes in Paediatric High grade glioma (pHGG), low grade glioma (pLGG) and medulloblastoma (MB) tumour tissue microarrays (TMAs). The antibodies detected protein expression of the metaboliser Arginase (Arg2), recycling enzymes ornithine transcarbamoylase (OTC), Arginosuccinate synthetase (ASS1) and arginosuccinate lyase (ASL) as well as the transporter SLC7A1. RESULTS Deficiency of OTC, ASS1 and ASL were seen in 92%, 98% and 93% of pHGG samples (n=156) respectively, with deficiency defined as low (<20%) or negative antibody expression. Identical results were seen in pLGG (n=98) - 83%, 97% and 95% were deficient in OTC, ASS1 and ASL. Both pHGG and pLGG highly expressed SLC7A1 and Arg2, demonstrating that they could transport and utilise arginine. In MB (n=82), this auxotrophic signature was again seen in 90% of TMAs with absent or low expression of OTC, ASS1 and ASL and high Arg2 and SLC7A1 expression. CONCLUSIONS These results show that pHGG, pLGG and MB are arginine auxotrophs. Pegylated arginase (BCT-100) is currently in Phase I/II trials in relapsed pHGG. Our results suggest that therapeutic arginine depletion may also be useful in MB and pLGG.

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Recent Developments of 18F-FET PET in Neuro-oncology

Current Medicinal Chemistry ◽

10.2174/0929867325666171123202644 ◽

2018 ◽

Vol 25 (26) ◽

pp. 3061-3073 ◽

Cited By ~ 17

Author(s):

Barbara Muoio ◽

Luca Giovanella ◽

Giorgio Treglia

Keyword(s):

Differential Diagnosis ◽

Brain Tumours ◽

Recent Literature ◽

Metabolic Imaging ◽

Low Grade ◽

High Grade ◽

Fet Pet ◽

Recent Developments ◽

High Grade Gliomas

Background: From the past decade to date, several studies related to O-(2- [18F]fluoroethyl)-L-tyrosine (18F-FET) positron emission tomography (PET) in brain tumours have been published in the literature. Objective: The aim of this narrative review is to summarize the recent developments and the current role of 18F-FET PET in brain tumours according to recent literature data. Methods: Main findings from selected recently published and relevant articles on the role of 18F-FET PET in neuro-oncology are described. Results: 18F-FET PET may be useful in the differential diagnosis between brain tumours and non-neoplastic lesions and between low-grade and high-grade gliomas. Integration of 18F-FET PET into surgical planning allows better delineation of the extent of resection beyond margins visible with standard MRI. For biopsy planning, 18F-FET PET is particularly useful in identifying malignant foci within non-contrast-enhancing gliomas. 18F-FET PET may improve the radiation therapy planning in patients with gliomas. This metabolic imaging method may be useful to evaluate treatment response in patients with gliomas and it improves the differential diagnosis between brain tumours recurrence and posttreatment changes. 18F-FET PET may provide useful prognostic information in high-grade gliomas. Conclusion: Based on recent literature data 18F-FET PET may provide additional diagnostic information compared to standard MRI in neuro-oncology.

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Elevated 2HG does not cause features of tumorigenesis

Neuro-Oncology ◽

10.1093/neuonc/noab195.000 ◽

2021 ◽

Vol 23 (Supplement_4) ◽

pp. iv1-iv1

Author(s):

Julie Adam ◽

Alina Finch ◽

Catarina Sepulveda ◽

Martin Ducker ◽

Maria Blanca Torroba ◽

...

Keyword(s):

Brain Tumours ◽

Driver Mutations ◽

Low Grade ◽

Causative Role ◽

Dna Amount ◽

Knock Out ◽

Cellular Analysis ◽

Enzymatic Function ◽

Mouse Tissues

Abstract Aims Gliomas are the most frequent brain tumours, representing 75% of all primary malignant brain tumours in adults. IDH1 (and IDH2) driver mutations occur in >80% of low grade gliomas and secondary GBMs, in <10% of primary GBMs and other cancers. How IDH1/2 mutations contribute to tumorigenesis is mostly unknown. IDH1/2 convert isocitrate to α-ketoglutarate, but when mutated possess a novel enzymatic function that reduces α-ketoglutarate to D2-hydroxyglutarate (2HG). Indeed 2HG accumulates in IDH1/2-mutant tumours, and this discovery suggested that 2HG may have a role in IDH1/2-mutant tumours onset and progression, possibly by causing dysregulations of various enzymes in the cells. Studies are undergoing to clarify the causative role of 2HG in IDH1/2-mutant tumours, but it is still not clear whether 2HG is the driver/oncometabolite. Our aim is to understand the role of 2HG in developing and adult mouse tissues and whether its accumulation might cause features of gliomagenesis. Method A constitutive D2hgdh Knock-out mouse (D2hgdh KO) was generated and the relative molecular and cellular analysis were performed. Results Brains dissected from D2hgdh KO mice appeared to be histologically normal. No differences were found in the proliferation and labelling retaining capacity of neural stem and progenitors cells (NSC/NPC) of the D2hgdh KO mice compared to controls. A comprehensive metabolites analysis showed that D2hgdh KO mouse accumulated 2HG in various organs and tissues, included total brains and in the NSC/NPC microdissected from the subventricular zone, the site of origin of many human gliomas. The DNA amount of 5mC and 5hmC extracted from brains of D2hgdh KO mice was similar to controls. A normal number of haematopoietic progenitors was also found. Conclusion Although D2hgdh KO mice accumulated 2HG in all tissues analysed, they did not develop any abnormalities and remained completely asymptomatic. This suggests that a mere increment of 2HG in developing and adult tissues may be not sufficient to cause tumorigenesis (and gliomagenesis), leading some doubts on the oncogenic roles of the 2HG in IDH1/2-mutant tumours.

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Clinical value of amino acid imaging in paediatric brain tumours

Nuklearmedizin ◽

10.1055/s-0038-1625755 ◽

2005 ◽

Vol 44 (04) ◽

pp. 131-136 ◽

Cited By ~ 3

Author(s):

K. Lang ◽

S. Kloska ◽

R. Straeter ◽

C. H. Rickert ◽

G. Goder ◽

...

Keyword(s):

Amino Acid ◽

Brain Tumours ◽

Photon Emission ◽

Diagnostic Tools ◽

Emission Computed Tomography ◽

Gadolinium Enhancement ◽

Tumour Grading ◽

Enhanced Mri ◽

Contrast Enhanced ◽

Paediatric Brain Tumours

Summary Purpose: To evaluate single photon emission computed tomography (SPECT) using the amino acid l-3-[123I]-α-methyl tyrosine (IMT) and contrast enhanced magnetic resonance imaging (MRI) as diagnostic tools in primary paediatric brain tumours in respect of non-invasive tumour grading. Patients, materials, methods: 45 children with primary brain tumours were retrospectively evaluated. IMT uptake was quantified as tumour/nontumour- ratio, a 4-value-scale was used to measure gadolinium enhancement on contrast enhanced MRI. Statistical analyses were performed to evaluate IMT uptake and gadolinium enhancement in low (WHO I/II) and high (WHO III/ IV) grade tumours and to disclose a potential relationship of IMT uptake to disruption of blood brain barrier as measured in corresponding MRI scans. Results: IMT uptake above background level was observed in 35 of 45 patients. IMT uptake was slightly higher in high grade tumours but the difference failed to attain statistical significance. Grading of individual tumours was neither possible by IMT SPECT nor by gadolinium enhanced MRI. Conclusion: IMT is accumulated in most brain tumours in children. Tumour grading was not possible using IMT or contrast enhancement as determined by MRI. Neither morphological nor functional imaging can replace histology in paediatric brain tumours.

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