Pediatric Low Grade Gliomas (pLGGs) are the most common pediatric brain tumours. Among them, non-resectable tumours remain a major clinical challenge due to the high frequency of relapses. Residual or recurrent tumours can be treated with radiotherapy or chemotherapy regimens, however these approaches are non-curative and carry significant risks and side effects.
Despite progress in understanding the molecular landscape of pLGGs, the underlying cell signaling mechanisms that sustain their growth are not fully understood, therefore recent studies started to explore the clinical utility of epigenetic changes in Central Nervous System (CNS) tumours.
The purpose of this project is to provide an insight into the molecular pathology of pLGGs to open new perspectives in pLGG therapeutic targeting through the discovery of microRNAs involved in their initiation and progression. To fulfill this aim, I will perform microRNA profiling on fresh-frozen samples of 45 grade I tumors resected from patients aged
pLGGs are the most common subtype of tumours that arise in the developing brains of children. Non-resectable pLGGs are highly frequent and associated with extensive morbidities, a large proportion of survivors show indeed long-term neurocognitive and psychosocial deficits. They include, but are not limited to, growth hormone deficiency, epilepsy, vision loss, impaired motor skills, memory dysfunction and reduced IQ, devastating outcomes that make critical the improvement of long-term outcome for survivors (Sexton-Oates et al., 2015). In recent years, next generation sequencing technologies have helped in understanding genetic lesions typically expressed in these tumours, holding promise as potential targets for novel therapies. However, since the clinical course of pLGGs is more similar to that of a chronic disease and the most commonly used chemotherapeutic agents often cause extensive morbidity, there is an urgent need in the development of new treatment strategies with the aim of reducing morbidity rather than increase survival. The discovery of epigenetic variations could play a pivotal role in the treatment of pLGGs. In this context, microRNAs have been highlighted as key players in tumour development, progression and/or recurrence. However, due to the high histological heterogeneity of pLGGs and to the complexity in obtaining fresh frozen tumour samples free from healthy tissue, data already available on microRNAs in pLGGs are scanty and far from conclusive. This project aims to trigger a fundamental transformation in the management of the huge proportion of pLGGs not amenable of complete surgical resection that still are a major clinical challenge. With this study, I propose to unravel microRNAs involved in the initiation and progression of pLGGs in order to identify novel potential candidates for molecular therapeutic targeting, opening new perspectives in pLGGs treatment. MicroRNAs could be applied not only in clinical trials as single treatment agents to obtain more effective and less toxic therapies, but also in combination with conventional chemo-radiotherapy to sensitize cancer cells. Furthermore, until now the absence of patients-derived cellular models of pLGGs has represented the main hurdle for an accurate study of their biology. Thanks to the primary patients' derived cells we established in the laboratory, I will have the chance to use short-term primary pLGG cells as cellular models to analyse the biological effects underlying the modulation of the microRNAs of interest in order to define their relevance in the tumorigenic signal activation and/or maintenance.
REFERENCES
Sexton-Oates A. et al., Annals of Oncology 2015