|Tipo di tesi||Tesi di dottorato di ricerca|
|Titolo||Approcci combinati di terapie a base di cellule staminali per l’adenocarcinoma pancreatico|
|Titolo in inglese||Combined approaches of a stem cell-based therapy for pancreatic adenocarcinoma|
|Settore scientifico disciplinare||MED/06 - ONCOLOGIA MEDICA|
|Corso di studi||MEDICINA MOLECOLARE E RIGENERATIVA|
|Data inizio appello||2017-03-10|
|Disponibilità||Accessibile via web (tutti i file della tesi sono accessibili)|
Il Tumore del Pancreas (TP) è la quarta causa di morte per cancro nei paesi occidentali, caratterizzato da più di 100.000 nuovi casi all’anno in Europa e un tasso di mortalità superiore al 90%. Ultimamente, le terapie avanzate basate sulle cellule e le terapie geniche stanno emergendo grazie a una migliore comprensione dell’architettura del tumore e delle alterazioni a carico delle cellule tumorali. Il nostro gruppo ha recentemente dimostrato l’efficacia di un approccio innovativo per il TP basato su Cellule Stromali Mesenchimali (MSC) ingegnerizzate geneticamente per produrre TNF-related Apoptosis Inducing Ligand (TRAIL).
Pancreatic Cancer (PC) is the fourth leading cause of cancer death in western countries characterized by more than 100,000 new cases per year in Europe and a mortality rate higher than 90%. In this scenario, advanced therapies based on cells and gene therapies are emerging thanks to a better understanding of tumor architecture and cancer cell alterations. We’ve recently demonstrated the efficacy of an innovative approach for PC based on Mesenchymal Stromal Cells (MSC) genetically engineered to produce TNF-related Apoptosis Inducing Ligand (TRAIL). In an effort to improve the potential of the treatment, also accounting for a possible resistance onset, we combined our MSC-based approach with administration of Paclitaxel-based chemotherapy. In addition, we created a gene therapy platform for the self-elimination of cells with the additional intent to control TRAIL production by MSC. Thus, we generated and characterized a TRAIL-resistant model of PC, starting from BXPC3 commercial cell line and tested the impact of the combined treatment in vitro with specific cytotoxicity and metabolic assays. Simultaneously, we created a viral vector encoding for a self-elimination gene that was used to modify MSC expressing TRAIL providing evidence of an elimination effect. We then further challenged our rationale in a subcutaneous mouse model of PC, assessing its effect on tumor size and by monitoring cancer cells with bioluminescence imaging technique. These results show that Paclitaxel has a remarkable cytotoxic activity on PC and is able to revert its pro-survival gene expression, thus restoring its sensitivity to TRAIL treatment. In this way, the two compounds synergize and combined treatment resulted in an improved cytotoxic effect on tumor cells. In addition, the self-elimination gene approach could be used to properly modulate TRAIL bioavailability impacting on both efficacy and safety of our strategy. In summary, this study supports the proof of concept of combining cell-based products and conventional chemotherapeutics as a mean to improve the efficacy and the safety of the treatments and possibly deal with resistance mechanisms.