Affinito, Alessandra (2017) Identification of selective aptamer ligands for Glioblastoma Stem Cells as new therapeutic tools for Glioblastoma. [Tesi di dottorato]

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Glioblastoma (GBM) is the most frequent and aggressive primary brain tumour in adults. Standard treatments for GBM patients consist of tumour resection, radiotherapy (RT) and chemotherapy with alkylating agent Temozolomide (TMZ). However, despite advances in surgical and medical treatment, prognosis for GBM patients remains dismal, with a median survival of 14–15 months. A small population of cancer stem cells (glioblastoma stem cells, GSCs), that retains stem cell properties including self-renewal and multipotency, has been implicated as responsible for the frequent relapse of glioblastoma and its resistance to conventional therapeutic. Thus, the identification of new molecules that can specifically target these GSCs is a fundamental challenge for the development of effective glioma therapies. In this study, we developed a differential whole cell-SELEX, an  in vitro  evolution-based approach, which allowed us to generate RNA-ligands with high affinity and specificity for GSCs, named aptamers. These nucleic acids were obtained by iterative evolution of a random pool of sequences using human primary GSCs as target. The obtained aptamer, 40L had been proved to be selective for GSCs, distinguishing them from tumor differentiated cells. Moreover, 40L revealed to be functionally active on target cells and able to inhibit stemness, cell growth and migration in vitro as well as in vivo. In conclusion, our results indicate that 40L and its short form A40s can selectively target GSCs and, given the crucial role of these cells in GBM recurrence and multi-drug resistance, 40L and A40s represent innovative drug candidates with a great potential in the GBM treatment.

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