Targeting mitochondrial bioenergetics and calcium to fight human diseases: from neurological disorders to cancer
Speaker: Beatrice Dorsi, PhD
Date: 10th November 12:30h
Place: Salón de Actos Jerónimo Forteza CIPF
Ca2+ homeostasis impairment and mitochondrial dysfunctions are the leading cause of neuronal dysfunction in patients affected by neurological and chronic neurodegenerative disorders, including stroke, epilepsy, Alzheimer’s disease and so on. In the last few years, I have demonstrated, for the first time, the role of the family of calcium-dependent proteases, calpains, and the pro-apoptotic members of the Bcl-2 family proteins, Bax and Bok, in excitotoxic/ischemic and seizure-induced neuronal injury both in vitro and in vivo, and investigated the authentic connection between mitochondrial Ca2+ overload, through the Mitochondrial Calcium Uniporter (MCU), and neurological conditions. To this end, the main goal throughout my research career has been to understand the aetiology of disease to identify new targets for therapeutic intervention towards the treatment of these diseases.
My scientific interests over the years have also been focused in examining metabolic reprogramming in cancer, and specifically, how activating KRAS mutation and loss of TP53 remodel cancer metabolism leading to alterations in bioenergetics under metabolic stress conditions by modulating cellular ATP production, NADH oxidation, mitochondrial respiration and function.
Recently, I have joined the CPFR (Centro Pisano Flash Radiotherapy in Pisa, Italy), which is equipped with a novel ElectronFlash LINAC accelerator capable of delivering very fast and highly energetic electron beams that selectively spares healthy tissue while leaving unchanged the therapeutic effect on tumor cells. FLASH radiotherapy (FLASH-RT) has attracted scientific interest because of its potential to revolutionize radiotherapy in terms of clinical, economic and social benefits. In fact, FLASH-RT has the potential to be effective also against tumors with unfavourable prognosis, and the duration of the treatment would be reduced from several sessions to one or very few. While the use of this innovative approach will certainly be ground-breaking in clinics, the physical and biological effects have yet to be fully explored. Using the FLASH-LINAC accelerator, preliminary toxicity tests have been carried out in two different cellular models (a primary human retinal pigment epithelial cell line ARPE-19 and murine glioma GL261 cells) and we are currently performing experiments to assess the radiobiological acute/early or long-term effects of ionizing radiation in vitro and in vivo in healthy, melanoma- and glioblastoma-bearing mice. Thus, we aim to acquire preclinical data in vivo and adapt the ElectronFlash LINAC for clinical use in a feasibility and safety study of FLASH-RT in patients with cancer.