Pediatric low grade gliomas (pLGG) are the most common central nervous system (CNS) tumors accounting for 30% of primary brain tumors below the age of 18 years.
Surgical resection is the first-line treatment and has been associated with a good long-term prognosis. However, their site of onset has a major impact on outcome, since it determines the tumor¿s resectability. About 30% of pLGG are located in areas of the brain (supratentorial/midline), where only a partial resection is feasible. Unfortunately, after partial resection, 30% of pLGG tumors relapse or progress. These tumors are treated with conventional chemotherapy and/or radiotherapy, treatments that are associated with detrimental consequences and substantial long-term toxicity. Moreover, pLGG can rarely present with metastases at the time of diagnosis and transform in high grade gliomas.
A deeper understanding of the molecular mechanisms underpinning these tumors will contribute to the stratification of the patients into prognostic risk categories that will help in avoiding unnecessary treatments. Therefore the main purpose of this project is to unveil biological information as well as to provide tools useful for the development of new targeted therapies. This proposal is based on preliminary results and the state of the art in pLGG research, suggesting the role of epigenetics and tumor microenvironment in the different behavior of pLGG tumors.
The proposed research will have an impact on cancer since it aims to identify innovative ¿integrated¿ features of pLGG maintenance to improve diagnosis and classification and ultimately provide insights for the development of targeted therapies.
pLGGs are the most common subtype of tumors 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 [1]. In recent years, next generation sequencing technologies have helped in understanding genetic lesions typically expressed in these tumors, 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 tumor development, progression and/or recurrence. However, due to the high histological heterogeneity of pLGGs and to the complexity in obtaining fresh frozen tumor samples free from healthy tissue, data on microRNAs in pLGGs are few and far from conclusive. Even less is known about the microRNAs-tumor microenvironment crosstalk and how the deregulated microRNA expression levels affect the glioma microenvironment. 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, the PI proposes 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, thanks to the set up of primary patients¿ derived cells the PI will use short-term primary pLGG cells as cellular models to analyze the biological effects underlying the modulation of the microRNAs of interest in order to define their relevance in tumor progression.
1. Sexton-Oates A et al, Annals of Oncology 2015