SNS01-T modulation of eIF5A inhibits B-cell cancer progression and synergizes with bortezomib and lenalidomide

50 µg of plasmid DNA and 25 µg of siRNA were complexed with 9 µl of in vivo-jetPEI (N/P=6) in a total volume of 1 ml of 5 mmol/l of Tris (pH 7.4) and 5% Glucose. Mice were treated by intravenous tail vein injection with 0.09 mg/kg to 0.75 mg/kg of complexes to target B cell cancer xenografts (Multiple Myeloma, diffuse large B-cell lymphoma, mantle cell lymphoma). Injections were repeated twice weekly for 6 weeks.

The high rates of recurrence and low median survival in many B-cell cancers highlight a need for new targeted therapeutic modalities. In dividing cells, eukaryotic translation initiation factor 5A (eIF5A) is hypusinated and involved in regulation of protein synthesis and proliferation, whereas the non-hypusinated form of eIF5A is a potent inducer of cell death in malignant cells. Here, we demonstrate the potential of modulating eIF5A expression as a novel approach to treating B-cell cancers. SNS01-T is a nonviral polyethylenimine-based nanoparticle, designed to induce apoptosis selectively in B-cell cancers by small interfering RNA-mediated suppression of hypusinated eIF5A and plasmid-based overexpression of a non-hypusinable eIF5A mutant. In this study, we show that SNS01-T is preferentially taken up by malignant B cells, inhibits tumor growth in multiple animal models of B-cell cancers without damaging normal tissues, and synergizes with the current therapies bortezomib and lenalidomide to inhibit tumor progression. The results collectively demonstrate the potential of SNS01-T as a novel therapeutic for treatment of a diverse range of B-cell malignancies.