Overcoming Drug Resistance to Treat High-Risk Neuroblastomas
Abstract
The ultimate goal of this project is to develop a more effective yet less toxic therapy to treat children with high-risk neuroblastoma, and potentially other patients with high-risk solid tumors. We have developed a novel multivalent macromolecule, PEG-[SN22]4, that candeliver 50 times more drug to the tumor than an equivalent dose of the conventional drug, irinotecan. We can cure most or all mice in NB in mouse models with 4 weekly doses, when irinotecan cures none. Efficacy of PEG-[SN22]4 used alone or in combination will be compared to comparable doses of free or liposomal CPT-11. PEG-[SN22]4 should not only be more effective than equivalent conventional agents, but also it has been designed to produce less systemic toxicity. It is long-circulating, so exposure to normal tissues and organs is reduced, and it has been chemically modified to avoid the most common dose-limiting toxicity experienced by patients, intractable diarrhea. However, we need to demonstrate this in animal models. We also plan to investigate other agents with which PEG-[SN22]4 maybe additive or synergistic, without significantly increasing toxicity. To date, we have shown considerable efficacy, curing most or all mice in transgenic, orthotopic, and PDX models, with excellent drug delivery and limited side effects.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2022
- Accession Number
- AD1191071
Entities
People
- Garrett M Brodeur
- Michael Chorny
Organizations
- Children's Hospital of Philadelphia