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

Abstract

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.

Pathological implications of metabolic reprogramming and its therapeutic potential in medulloblastoma

“…AMPK and mTORC1 exert their function through the regulation of autophagy, a fundamental process that allows the recycling of intracellular components through their lysosomal-dependent degradation. Autophagy is a key survival process induced by nutrient stress and upregulated in several types of cancers, including high-risk MB ( Nazio et al, 2019 , 2021 ; Paul et al, 2020 ; Gatto et al, 2021 ). It has recently been demonstrated that autophagy activation in Group 3 MB supports stemness and metastasization ( Nazio et al, 2021 ).…”

Repurposing autophagy regulators in brain tumors

“…Similar to adults, brain tumors affecting children and adolescents exhibit susceptibility to dysregulations in autophagy, both as a result of its induction and inhibition. 109 In a set of medulloblastoma cellular models, autophagy inhibition was shown to impede the tumor growth and to reduce its invasive capacity. 110,111 At the same time, targeting mTOR in medulloblastomas was also found to be effective.…”

“…Therapeutic regulation of autophagy is increasingly generating an interest within the scientific community studying pediatric brain cancer as well. Similar to adults, brain tumors affecting children and adolescents exhibit susceptibility to dysregulations in autophagy, both as a result of its induction and inhibition 109 . In a set of medulloblastoma cellular models, autophagy inhibition was shown to impede the tumor growth and to reduce its invasive capacity 110,111 .…”

The Role of Autophagy in Childhood Central Nervous System Tumors

“…For medulloblastoma, MirR-30a inhibited autophagy by reducing beclin 1/ATG5 expression and was linked to increased cell death in a medulloblastoma cell line [ 74 ]. Until now, there have only been a few clinical trials for autophagy modulators in treatment of childhood CNS tumors [ 75 ] (Table 1 ). Hydroxychloroquine combined with Dabrafenib (NCT04201457), everolimus (NCT00187174), everolimus combined with lenvatinib (NCT03245151), and Temsirolimus combined with valproic acid (NCT01204450) were used in clinical trials as modulators of induced autophagy in the treatment of childhood CNS tumors [ 76 – 79 ].…”