Project 2: Therapeutic Combination of CLR1404 with External Beam Radiation in Head and Neck Cancer

项目摘要 放射是头颈癌（HNC）治疗的主要方式，大约三分之二的患者接受放射治疗。 在最终、辅助或姑息环境中接受放射治疗的患者。虽然技术上 已经在具有3D适形和强度的辐射的递送和剂量成形方面取得了进展， 在调制式放射治疗（IMRT）中，正常组织毒性仍然是剂量限制性的。在目前的提案中，我们 将测试一种有前途的新的放射性标记分子（CLR 1404），该分子是在过去十年中在纽约大学开发的。 威斯康星州。CLR 1404是一种放射性标记的磷脂分子，具有强大的成像潜力 （用124 I标记）和作为治疗剂（用131 I标记）。CLR 1404显示出有效的摄取和保留， HNC从而提供放射的肿瘤选择性内部递送以补充体外射束放射， HNC的治疗。我们的假设是，CLR 1404将在HNC模型系统中诱导肿瘤应答， 在复发性HNC患者的I期临床试验中证明了良好的耐受性和反应特征， 结合外部光束辐射。我们的三个具体目标是：1）检查吸收和保留 2）量化CLR 1404在小鼠模型中跨一组HNC异种移植物的能力， HNC异种移植模型系统中的外部束辐射反应，和3）进行I期临床试验， CLR 1404联合低剂量外照射治疗局部复发患者 之前的HNC辐射。这项试验将检查可行性，毒性，肿瘤反应，唾液和 吞咽功能和HN特异性生活质量（QOL）。我们将强调使用PET-124 I-CLR 1404的用途。 CT成像是指导后续131 I个性化治疗处方的理想生物标志物- CLR1404。本研究具有创新性和重要意义，因为它是第一个研究结合外部 放射线照射加CLR 1404内照射治疗HNC患者。外束去增强 辐射剂量，减少正常组织毒性，所以常见的HNC患者，支持最终的 目的提高高血压性神经营养不良（HNC）患者的治疗效果和生活质量。

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.