Filippo Torrisi

Ciclo: XXXIII

Data inizio: 31/10/2017

Curriculum: Biomediche e Precliniche

Borsa: UniCT

Titolo tesi: SRC inhibition combined with radiotherapy and proton therapy: a synergistic strategy for glioblastoma treatment

Abstract: In the field of neuroncology, radiation therapy has clearly acquired a central role for the treatment of aggressive tumors, such as GlioBlastoMa (GBM). GBM is the most common. The aim of this project was to evaluate the synergic radiosensitive effect of a new SRC inhibitor (Si306, Lead Discovery Siena) in combination with radiation therapy for GBM treatment. In a first work, Si306 was tested with proton therapy, demonstrating a radiosensitive effect. Proton therapy experiments were performed at the National Institute for Nuclear Physics, Laboratori Nazionali del Sud, (INFN-LNS) in Catania. Clonogenic assay and molecular pathways analysis were performed to evaluate the surviving fraction and the cell network modulation respectively, confirming the effectiveness of proton therapy in combination with the Si306. In a second work, the radiosensitive effect of Si306, in combination with X-rays irradiation, was evaluated comparing normoxic (21% of oxygen) and hypoxic (1% of oxygen) conditions. In addition to clonogenic assay, γH2AX molecular marker detection by immunofluorescence was performed to quantify the radiation-induced DNA double-strand break formation and the DNA damage repair ability. The role of SRC inhibition on migration was also evaluated by wound healing assay. These experiments were performed at the research unit “Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales” (ISTCT), located in the Cyceron center of Caen, France. It was demonstrated that Si306 exhibited a synergistic effect with X-rays, decreasing radioresistance induced by hypoxia. malignant and radioresistant brain tumor in adults, characterized by an exiguous life expectancy, with median survival of 6–12 months after diagnosis. The radioresistance of GBM is mainly determined by the occurrence of hypoxic regions, where the indirect effects of ionizing radiation are largely reduced. Moreover, hypoxia is involved in the activation of intracellular signaling pathways mediated by SRC proto-oncogene non-receptor tyrosine kinase (SRC), that leads to proliferation, migration and invasion effects. For this reason, new molecularly targeted drugs for SRC inhibition combined with radiation therapy could increase the effect of ionizing radiation (X-rays for radiotherapy and protons for proton therapy or hadrontherapy), blocking specific pathways of radioresistance. In conclusion, while further in vitro and in vivo investigations are required, the encouraging data confirms Si306 as a novel putative drug to overcome GBM radioresistance.

Tutor: Parenti

Data Conseguimento Titolo: 29/03/2021

Linkedin: Indicate il link

Email: ftorrisi89@gmail.com

Periodi all'estero- Sede e data: Si

Esperienze post-Dottorato ed attuale occupazione: Dal 01/03/2022 al 15/01/2023: Ricercatore “Post-Doctoral Fellowship – Anno 2022, Fondazione Umberto Veronesi. Dal 16/02/2021 al 16/02/2022: Assegnista di ricerca post doc presso Università degli studi di Catania. Dal 16/03/2023 ad oggi: Ricercatore a tempo determinato di tipo A, Fisiologia S.S.D. BIO/09 presso Università degli studi di Enna “Kore”, Facoltà di Medicina e Chirurgia