PROJECT SUMMARY Radiation is a central modality for Head and Neck Cancer (HNC) treatment with approximately two-thirds of patients receiving radiation in the definitive, adjuvant or palliative setting. Although significant technical advances have been made in the delivery and dose shaping of radiation with 3D-conformal and intensity modulated radiation therapy (IMRT), normal tissue toxicity remains dose limiting. In the current proposal, we will test a promising new radiolabeled molecule (CLR1404) developed over the last decade at the University of Wisconsin. CLR1404 is a radiolabeled phospholipid molecule with powerful potential as an imaging agent (labeled with 124I) and as a therapy agent (labeled with 131I). CLR1404 shows potent uptake and retention in HNC thereby providing tumor-selective internal delivery of radiation to complement external beam radiation in the treatment of HNC. Our hypothesis is that CLR1404 will induce tumor response in HNC model systems, and demonstrate a favorable tolerance and response profile in a Phase I clinical trial for recurrent HNC patients in combination with external beam radiation. Our three specific aims are: 1) Examine uptake and retention of CLR1404 across a panel of HNC xenografts in mouse models, 2) Quantify the ability of CLR1404 to augment external beam radiation response in HNC xenograft model systems, and 3) Perform a Phase I clinical trial that combines CLR1404 with reduced-dose external beam radiation in patients with locoregional recurrence following prior HNC radiation. This trial will examine feasibility, toxicity, tumor response, salivary and swallowing function, and HN-specific quality of life (QOL). We will highlight the use of 124I-CLR1404 using PET- CT imaging as the ideal biomarker to guide the subsequent personalized therapy prescription with 131I- CLR1404. This work is innovative and significant because it is the first study to examine combined external beam radiation plus internal radiation with CLR1404 in patients with HNC. De-intensification of external beam radiation dose, with reduction in normal tissue toxicities so common in HNC patients, supports the ultimate objective to improve treatment outcome and QOL for HNC patients.