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

项目总结 放射治疗是头颈癌(HNC)治疗的中心方式，大约三分之二的患者 在最终、辅助或姑息状态下接受放射治疗的患者。尽管在技术上意义重大 在三维共形和强度辐射的传输和剂量成形方面取得了进展 调强放射治疗(IMRT)，正常组织毒性仍受剂量限制。在目前的提案中，我们 将测试一种很有前途的新的放射性标记分子(CLR1404)，该分子是在过去十年中由加州大学开发的 威斯康星州。CLR1404是一种具有很强显像剂潜力的放射性标记磷脂分子 (标记有124I)和作为治疗剂(标记有131I)。CLR1404显示出强大的摄取和保留能力 HNC从而提供肿瘤选择性的内照射以补充外照射 HNC的治疗。我们的假设是CLR1404将在HNC模型系统中诱导肿瘤反应，并且 在对HNC复发患者的I期临床试验中显示出良好的耐受性和反应情况 与外束辐射相结合。我们的三个具体目标是：1)检查吸收和保留 CLR1404在小鼠模型中的一组HNC异种移植，2)量化CLR1404增强的能力 HNC异种移植模型系统中的外束辐射响应，以及3)执行I期临床试验， CLR1404联合减量外照射治疗局部复发 在先前的HNC辐射之后。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特有的生活质量(QOL)。我们将重点介绍使用PET的124I-CLR1404的使用。 CT是指导131I-核素个体化治疗处方的理想生物标志物 CLR1404。这项工作具有创新性和重要意义，因为它是第一个研究组合外部 高能电子束照射加CLR1404内照射治疗慢性粒细胞白血病外光束的退光化 辐射剂量，随着正常组织毒性的减少在HNC患者中如此普遍，支持了终极 目的提高高血压性鼻咽癌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.