A novel engineered exosome-mimetic immune-evading proteoliposome vehicle for siRNA-mediated targeting of PAX3-FOXO1 fusion oncoprotein in rhabdomyosarcoma

Description :

Oncogenic fusion proteins (such as the PAX3-FOXO1 protein in the pediatric tumor rhabdomyosarcoma) have been well characterized as cancer drivers. However, they have largely been considered untargetable by small molecule inhibitors. Use of small interfering RNA (siRNA) has shown promise in reducing expression of fusion oncoproteins in vitro, but its therapeutic application is limited by the rapid degradation of RNA in blood. Attempts to deliver siRNA via encapsulation within liposomes has been challenging due to clearance of liposomes by the immune system, with limited uptake by tissue. Recent work suggests that exosomes, which are small, membrane-bound vesicles secreted and taken up by all types of cells, may be used to deliver siRNA against oncogenes as well as cytotoxic drugs to tumor cells in vivo, and the exosome surface protein CD47 was found to be essential for their enhanced evasion of the immune response. However, exosome isolation and manipulation is technically demanding, posing challenges against their use in clinical therapeutics. We propose to evaluate the feasibility and efficacy of a novel platform of modified liposomes, in delivering siRNA against fusion oncoproteins, using PAX3-FOXO1-positive rhabdomyosarcoma as a model.