Impairing Importin α5- Mediated Nrf2 Nuclear Translocation as a Novel Strategy for Treating Chemoresistant Medulloblastoma

Medulloblastoma is one of the most common brain tumors in pediatric age and is characterized by fast proliferation and high invasiveness. Although in recent years the therapeutic treatments have been improved, recurrence occurs in approximately 30-40% of cases. Unfortunately, recurrence is typically associated with the development of chemotherapy resistance which remains an obstacle in patients care and significantly decreases the overall survival. Our research group has developed and thoroughly characterized a new in vitro model of chemotherapy-resistant medulloblastoma cell line (MB-R). Multiomic analysis of the MB-R line revealed a distinct molecular profile marked by significant alterations in cellular metabolism compared to their chemotherapy-sensitive counterparts. Later, further analysis showed that cancer cells, particularly those resistant to therapy, present altered ROS scavenging systems. These changes involve the upregulation of antioxidant systems aimed at maintaining low ROS levels to prevent oxidative damage induced by chemotherapeutics. In this thesis work, we deepened the role of Nrf2, considered the main cell antioxidant system, in the emergence of resistance to chemotherapy. In addition, we found that Nrf2 pathway is induced by chemotherapy itself through a hormetic response that involves the generation of intracellular ROS. Collectively our data suggest Nrf2 as a useful target to be inhibited to improve the efficacy of chemotherapy and reduce the risk of relapse. In collaboration with Professor Matteo Borgini from Augusta University, we tested synthetic peptides capable of inhibiting the nuclear translocation of Nrf2 by disrupting its interaction with Importin a5. The biological effect of the new series of peptides has been evaluated through the analysis of Nrf2 cellular localization, the expression of Nrf2 target genes, and the setup of a FRET assay. As a result, we identify new putative Nrf2 inhibitors able to 6 reduce the ability of medulloblastoma cells to scavenge redox stress induced by chemotherapy.