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 project aims to identify circulating plasma biomarkers of pLGG patients to allow early detection of disease, predict progression and / or response to surgical and / or pharmacological therapy. Starting from the results obtained from the microRNAs profile in my previous work, I will proceed to confirm the presence in the plasma of the microRNAs found up-regulated in the diseased tissues compared to the control tissues. Subsequently, a prospective study will be performed, recruiting plasma of pLGG to the diagnosis and after 6 months from the operation. For these patients also the levels of the identified microRNAs will be evaluated in order to define the first circulating biomarkers of low-grade pediatric gliomas.
pLGGs are the most common subtype of childhood tumours that arise in the developing brain. 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 of healthy tissue contamination, 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 pLGGs through the identification of microRNAs as circulating biomarkers using liquid biopsy.
Liquid biopsy is currently considered the new frontier in the treatment of oncological diseases. Through this kind of approach it is possible to meet the realization of the greatest current objective in the clinical field: precision medicine. The identification of circulating biomarkers that would allow diagnosis, classification, and response to treatment prediction would represent a turning point in cancer prevention and / or treatment. Using a blood sample to achieve this goal would drastically reduce the still too high costs necessary for the clinic, while it would breathe a sigh of relief to patients, being a non invasive method. Liquid biopsy has been successfully tested on different types of cancer, such as lung cancer, but thesehas been no application in the field of pediatric gliomas. The innovativity of this project lies in the use of one of the most topical experimental techniques in an almost unexplored and complex oncological context. Through the analysis of the components present in the plasma of individual patients, it will be possible to identify specific biomarkers that will allow to diagnose, recognize and / or stave the tumor, something that is currently only possible through surgery. In addition, complementary to the diagnosis, the liquid biopsy will allow the patient to be provided with an ad personam drug treatment, being able to identify 'response' biomarkers. Finally, following the patients over time it would be possible to identify the possibility of recurrence, thus being able to characterize in advance which tumor and how it will manifest again.