Norepinephrine Transporter-Targeted Pharmacotherapy of Aggressive Neuroblastoma
NB remains one of the deadliest solid tumors in children. Over half of high-risk NB patients experience relapse with no curative rescue treatment options. Topoisomerase I inhibitors of the camptothecin family are among the most potent anticancer agents effective against many pediatric solid tumors. However, they often show poor efficacy against high-risk NB due to difficulty in achieving and maintaining stable drug presence at sufficient levels in the tumor while avoiding dose-limiting adverse effects. We evaluated in this project a new prodrug-based strategy designed to provide efficient targeted delivery of a potent camptothecin analog to NB tumors. This approach is unique in combining several layers of selectivity, together directing and restricting the drug effect to actively dividing NB tumor cells, while minimizing toxicity to normal tissues. Using models of refractory high-risk disease, we investigated tumor uptake and therapeutic efficacy of our experimental prodrug. Prodrug-based targeted delivery resulted in enhanced uptake and prolonged intratumoral presence of a potent anticancer agent at levels ≥ 100 times greater than those required to efficiently suppress growth of chemoresistant NB tumors. Consistent with these results, the prodrug caused rapid regression of aggressive NB tumors and markedly extended survival in several preclinical models of high-risk disease. The results of our studies demonstrate feasibility and effectiveness of targeted NB therapy using prodrug agents designed to exhibit enhanced tumor selectivity. These studies are an important step toward the development of a new, more effective and safer way of treating drug-resistant NB and other aggressive malignancies in children.
Project Goal
The present studies focus on an experimental treatment with enhanced pharmacological selectivity using polymer-liked prodrugs to deliver a potent chemotherapeutic agent chemically functionalized for tumor cell targeting. If proven effective, this polymeric prodrug-based approach can provide a means to suppress aggressive tumors without causing major toxicity often seen with traditional chemotherapy.
