Enhancing drug delivery to treat high-risk neuroblastoma

About This Grant

Abstract This project focuses on macromolecular prodrug-based delivery of a topoisomerase I inhibitor, SN22, structurally enhanced to overcome tumor defense mechanisms in order to achieve durable suppression of high-risk neuroblastoma (NB), the most common and deadly solid tumor of childhood. The intensive, multimodality treatment currently used clinically fails in over half of high-risk NB patients: 50-60% experience a relapse with no curative salvage treatment options. Centered on developing and optimizing a drug delivery strategy against the aggressive disease not responding to conventional therapies, with a particular focus on a high-risk form of multiple drug-resistant NB with increased “stemness” driven by a MYCN protooncogene and its downstream target, ABCG2 (an ABC drug efflux pump suppressing chemosensitivity and promoting tumorigenicity), this project will evaluate an approach integrating polymer-linked prodrug design and structural optimization of the cargo to improve delivery, extend drug residence in the tumor, and reverse drug resistance. Guided by our past work and the results of our preliminary studies toward this project, we hypothesize that prodrug-mediated delivery of SN22 will potently suppress growth of aggressive, pre-therapy and chemorelapsed NB tumors by enhancing drug uptake and extending tumor exposure to therapeutically effective drug levels and by taking advantage of the inactivation-resistant molecular design of this agent. This hypothesis will be tested by pursuing the following specific aims: Aim 1 studies will focus on in vitro evaluation of a series of prodrug constructs on NB cells derived at relapse from MYCN-amplified high-risk NB tumors; Aim 2 studies will examine tumor uptake, biodistribution and elimination of the prodrugs in orthotopic xenograft NB models; Aim 3 experiments will comparatively evaluate antitumor efficacy of prodrug- mediated delivery in models of newly diagnosed and recurrent MYCN-amplified NB in comparison to a new syngenetic model of disseminated (MYCN-driven) high-risk disease. Through optimizing the design and performance of SN22 prodrugs using a panel of clinically relevant models recapitulating distinct types and phases of aggressive NB, this research is expected to have a strong impact on the field by addressing several barriers to the translation and clinical implementation of macromolecular prodrugs and by paving the way to improved clinical management of drug-resistant NB and other high- risk cancers showing minimal or no response to conventional therapies and currently lacking effective treatment options.