Project Funding Details

Glioblastoma (GBM) is the most common and malignant among gliomas with inevitable lethal outcome due to its cellular and molecular heterogeneity. Despite many advanced approaches in treating GBM patients, their average life expectancy remains about 15 months. There is an urgent need to identify key regulatory targets to devise more refined patient-specific therapeutics. In this context, gut microbiota composition has been shown to influence carcinogenesis, tumor progression and response to anticancer therapies. However, little is still known about its role in GBM patients. We hypothesize that a distinct gut microbiota signature discriminates GBM patients underlying the malignant phenotype and treatments' efficacy, representing an invaluable tool for the discovery of novel prognostic biomarkers and innovative, more effective, patient-tailored therapeutic targets. The identification of GBM patients' peculiar fecal microbiota and transcriptomic fingerprint will be a crucial tool to: 1) unveil new critical effectors for the determination of patient-tailored diagnostic and prognostic protocols; 2) the establishment of a predictive system to define patient's stratification and drug-responsiveness; 3) develop new biotherapeutic approaches, also in a combinatorial fashion, by manipulating the intestinal microbiota. Having preliminarily observed a specific microbial signature for GBM patients as compared to low-grade glioma, benign brain tumor and healthy subjects, we will expand and deepen our data exploring the involvement of gut microbiota in GBM malignant phenotype and treatments' efficacy. We will first pinpoint the peculiar GBM patients' fecal microbial signature and transcriptomic hallmarks, thus identifying new critical bacterial and molecular effectors discriminating these patients. Knowing by preliminary evidences that GBM-bearing mice display a patient-specific global alteration in the fecal microbiota profile, as compared to controls, we will identify in our clinically relevant, PDX model of human GBM novel bacterial biomarkers predicting GBM patient stratification, outcome and treatment sensitivity. Finally, having completed a phase I clinical trial with intra-parenchymal infusion of BMP4, which elicits pro-differentiation effects, in GBM recurrences and preliminary observed an inherently different resilience to BMP4 and TMZ within subtypes and a different microbiota signature after BMP4 infusion, we will test whether the differences in microbiota composition have a causative effect on the variable response to either standard first-line or to pro-differentiative therapies and overall survival. This will be done by fecal microbiota transplantation (FMT) studies from human fecal samples into mice, thus allowing for a potential translation into clinical trials. These objectives will be attended using a combination of our mouse model of human GBM, that can reliably mimic the characteristics of malignant cells and the features of the human disease, biomolecular, bioinformatics and high-throughput sequencing approaches. We expect to identify novel crucial predictive effectors involved in GBM pathophysiology needful for diagnostic and prognostic purposes and, mostly, to define innovative, efficacious and patient-tailored therapeutic approaches eliciting GBM patients' treatment response and overall survival through the manipulation of gut microbiota. The multifaceted approach is designed to translate molecular and in vivo data into new and exciting possibilities for GBM prognosis and into innovative experimental clinical application for individual patient-specific biotherapies.