Radiation therapy plays a critical role in the treatment of many adult and pediatric cancers. Improving the efficacy and safety of radiation therapy is a high priority. Two potential strategies to improve the therapeutic threshold for radiation are the use of targeted radionuclides and the use of radiation sensitizers. As a model for evaluating both of these strategies, we will focus on the targeted radionuclide, 131I- mIBG, for children with advanced neuroblastoma. Children with advanced neuroblastoma continue to have poor outcomes despite intensive multimodality therapy. To improve cure rates for these patients, novel targeted therapies are required. The targeted radionuclide 131I-mIBG is one of the most active agents for patients with advanced neuroblastoma and is therefore a high priority for further clinical development. This application for an R01 award includes two complementary aims designed to evaluate radiation sensitization in the context of a therapeutic radionuclide. In Aim 1, we will evaluate the strategy of using a systemic radiation sensitizer together with 131I-mIBG therapy. We will conduct a prospective multicenter three- arm phase II selection design clinical trial to identify the 131I-mIBG treatment regimen associated with the highest overall objective response rate. Patients with relapsed or refractory neuroblastoma will be randomized at study entry to one of three 131I-mIBG treatment arms: (1) single agent 131I-mIBG, (2) 131I-mIBG plus vincristine and irinotecan, or (3) 131I-mIBG plus vorinostat. The trial will be conducted within the NCI-sponsored New Approaches to Neuroblastoma Therapy (NANT) research consortium. The primary endpoint is overall objective tumor response after one course of therapy. A total of 105 patients will be treated, with 35 patients/randomized to each treatment arm. At the conclusion of the trial, the most active regimen will be incorporated into future studies for patients with newly diagnosed high-risk neuroblastoma. In Aim 2, we will evaluate a panel of markers of organ toxicity, DNA damage, and cellular response to DNA damage in patients treated on the clinical trial in Aim 1. Patients will provide blood samples at baseline and approximately 72 hours after 131I-mIBG infusion. We will use these samples to quantify serum amylase, plasma Flt3 ligand, lymphocyte ¿H2AX foci, and mRNA transcript for a panel of genes involved in response to DNA damage. We will evaluate the effect of 131I-mIBG with and without radiation sensitizers on these markers as a tool to understand the mechanism of radiation sensitization. While our emphasis is on 131I-mIBG therapy for neuroblastoma, our findings will have important implications for other applications. For example, 131I-mIBG is also used in the treatment of adults with pheochromocytoma. More generally, our work will inform other research focused on the use of radiation sensitizers and on development of novel biomarkers in patients receiving other forms of radiotherapy.