Targeted Therapy for Childhood Cancers Using siRNA and Nanoparticles - Bedside to Bench to Bedside -GCOE Program Seminar(Global Education Seminar)

We are developing a novel cancer-targeted therapy using short interfering RNA (siRNA) nanoparticles (NPs) with cancer-specific ligands to selectively target the Max dimerization protein 3 (Mxd3), which we believe is important for cell survival. We will test this novel therapeutic approach in human cancer xenograft mouse models using primary cancer tissue samples. We will create mouse models for acute lymphoblastic leukemia (ALL) and neuroblastoma, which are the two most common childhood malignancies. Using cell lines, we have developed an in vitro treatment targeting Mxd3 with siRNA: superparamagnetic iron oxide NP complexes (SPIO-NPs). We now propose to develop a novel Mxd3-targeted therapy with siRNA: SPIO-NPs and cancer-specific ligands in vivo. We are using the one-bead-one-compound (OBOC) combinatorial library method to identify cancer cell surface-targeting ligands. With OBOC libraries, millions of different beads can be synthesized, each bead bearing up to 1013 copies of the same molecule. We have identified several ligand candidates for ALL and neuroblastoma. We have established a new ALL xenograft mouse model of patients’ leukemia cells with NOD/SCID/IL2R-/- (NSG) mice. We have shown successful engraftment and maintenance of primary leukemia cells through serial transplantations by intra-bone marrow injection. We are currently developing a neuroblastoma mouse model. We will use these models to test our proposed targeted therapy directly on human cancer cells engrafted in the mice.