Harnessing the cellular and molecular complexity of high-risk neuroblastoma to investigate novel potential treatment approaches

De Rosa, Piergiuseppe (2023) Harnessing the cellular and molecular complexity of high-risk neuroblastoma to investigate novel potential treatment approaches, [Dissertation thesis], Alma Mater Studiorum Università di Bologna. Dottorato di ricerca in Biologia cellulare e molecolare, 35 Ciclo.
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Neuroblastoma (NB) is the most common type of tumor in infants and the third most common cancer in children. Current clinical practices employ a variety of strategies for NB treatment, ranging from standard chemotherapy to immunotherapy. Due to a lack of knowledge about the molecular mechanisms underlying the disease's onset, aggressive phenotype, and therapeutic resistance, these approaches are ineffective in the majority of instances. MYCN amplification is one of the most well-known genetic alterations associated with high risk in NB. The following work is divided into three sections and aims to provide new insights into the biology of NB and hypothetical new treatment strategies. First, we identified RUNX1T1 as a key gene involved in MYCN-driven NB onset in a transgenic mouse model. Our results suggested that that RUNX1T1 may recruit the Co-REST complex on target genes that regulate the differentiation of NB cells and that the interaction with RCOR3 is essential. Second, we provided insights into the role of MYCN in dysregulating the CDK/RB/E2F pathway controlling the G1/S transition of the cell cycle. We found that RB is dispensable in regulating MYCN amplified NB's cell cycle, providing the rationale for using cyclin/CDK complexes inhibitors in NBs carrying MYCN amplification and relatively high levels of RB1 expression. Third, we generated an M13 bacteriophage platform to target GD2-expressing cells in NB. Here, we generated a recombinant M13 phage capable of binding GD2-expressing cells selectively (M13GD2). Our results showed that M13GD2 chemically conjugated with the photosensitizer ECB04 preserves the retargeting capability, inducing cell death even at picomolar concentrations upon light irradiation. These results provided proof of concept for M13 phage employment in targeted photodynamic therapy for NB, an exciting strategy to overcome resistance to classical immunotherapy.

Tipologia del documento
Tesi di dottorato
De Rosa, Piergiuseppe
Dottorato di ricerca
Settore disciplinare
Settore concorsuale
Parole chiave
Neuroblastoma, MYCN, GD2, RB, E2F, RUNX1T1
Data di discussione
28 Marzo 2023

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