LAUSR

Potent kinase inhibitors have been developed to treat tumors, but they suppress signaling in normal cells so that their dosing and ability to inhibit the pathway are limited by toxicity, resulting in a narrow therapeutic index. We developed a novel drug delivery strategy which efficiently encapsulates and targets kinase inhibitors to the tumor microenvironment while obviating the sources of dose-limiting toxicities. The platform employs nanoparticle scaffolds that we modified to target caveolae and P-selectin, that can both be overexpressed on tumor vasculature. We assessed the targeted drug delivery properties of the nanoparticles, encapsulating the RAF inhibitor sorafenib and MEK inhibitor trametinib. Strikingly, we found selective tumor uptake and exceptional net anti-tumor efficacies in patient-derived xenografts and genetically modified mouse models. The nanomedicine strategy also prevented the inhibition of ERK phosphorylation in the skin, demonstrating that this targeting strategy may abrogate dose-limiting toxicities of kinase inhibitors to improve their therapeutic indices. Citation Format: Daniel A. Heller, Yosi Shamay. Targeted nanomedicines improve therapeutic indices of RAF and MEK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4652.