
Project details
ENU Team Leader: GABRIELLA NICOLINI
Other ENU members involved: ALESSIO MALACRIDA, MARIAROSARIA MILOSO, LAURA MOLTENI, OLGA TARASIUK
Coordinator: GABRIELLA NICOLINI
Funded by: FONDAZIONE ISTITUTO FARMACOLOGICO FILIPPO SERPERO ETS
Total Contribution: 85.000 €
Project Duration in months: 24
Start Date: July 6, 2023
End Date: July 6, 2025
Fondazione Serpero website: https://fondazioneserpero.it/
Abstract
Chemotherapy drug-induced peripheral neurotoxicity (CIPN) is one of the most frequent and serious long-term side effects of cancer chemotherapy. More than 50% of cancer patients treated with chemotherapy develop CIPN during or after completion of chemotherapy and in the majority of them this complication persists six months after treatment. CIPN represents a serious medical problem because it can cause reduction or interruption of chemotherapy treatment and induce difficult-to-treat symptoms that interfere with the quality of daily life. CIPN is generally a dose-dependent sensory neuropathy characterized by paresthesias/dysesthesias, loss of sensation, and sometimes accompanied by neuropathic pain. Less frequently CIPN shows motor or autonomic signs. Preclinical and clinical studies have extensively studied CIPN in search of effective strategies to limit its severity, but to date no recommended therapeutic gold standards for its prevention or treatment have been identified. CIPN is induced by anticancer drugs commonly used for both solid and blood tumors, characterized by different mechanisms of action such as platinum analogues (e.g. cisplatin and oxaliplatin), proteasome inhibitors (e.g. bortezomib), immunomodulators/ antiangiogenics (e.g., thalidomide) and taxanes (e.g., paclitaxel).
Histone deacetylases (HDACs) are enzymes that remove acetyl groups from lysine residues at the NH2 end of histones, remodeling chromatin and thus acting in the epigenetic regulation of gene expression. HDAC6 is one of the proteins of the HDAC family that not only participates in histone remodeling, but is capable of deacetylating several non-histone substrates that are involved in tumor proliferation, invasion and metastasis. Selective HDAC6 inhibitors are potent anticancer agents that are gaining increasing attention. Furthermore, for some HDAC6 inhibitors a neuroprotective effect has been demonstrated against neurons subjected to oxidative stress, a common aspect of damage in various neurological conditions. However, the exact mechanism of HDAC6 inhibitors is not yet clarified.
The project we propose aims to investigate the molecular mechanism through which HDAC6 inhibitors (commercially available) carry out their neuroprotective effect against neurotoxicity induced by chemotherapeutics that act with different mechanisms of action (cisplatin/oxaliplatin, vincristine, paclitaxel and bortezomib). Specifically, we will study the involvement of the NMNAT2/SARM1 pathway using primary cultures of adult mouse sensory neurons, a model widely used in the literature for the study of peripheral neurotoxicity.