Intraoperative Molecular Imaging of Pulmonary Squamous Cell Carcinoma

项目摘要 癌症继续影响着广泛的人群，死亡人数超过60万 预计今年在美国的恶性肿瘤。[1]完整的手术切除，如 与单独的化疗或放疗相比， 治愈大多数实体瘤的可能性。然而，局部和全身复发影响40%的 因疾病清除不完全和阳性而接受根治性切除术的患者 在指数操作的利润率。[2]以帮助完成癌症切除， 提高患者存活率-术中分子成像（IMI）已被视为 肿瘤外科重要新工具。这项技术使用荧光，肿瘤靶向 示踪剂，以确定阳性边缘和术前未识别的疾病部位。IMI拥有 近年来应用于胸部肿瘤。[3]然而，在以下方面仍有一项重大需求未得到满足： 肺鳞状细胞癌，是第二常见的肺癌亚型 5年生存率特别低，为17.6%。[4]美国 这是一个翻译的建议，其主要目标是开发和优化一个光学 SCC的分子成像探针。我们的目标是合成一种靶向EGFR的近红外（NIR） 示踪剂是特定的SCC和生物相容性，使用我们的实验室建立的方法，并通过 亲密的合作者首先在体外评价示踪剂：1）受体结合亲和力，2） 非特异性结合（与过量未标记配体竞争），3），水溶性，4）血清 蛋白质结合和5）光和化学稳定性。靶向NIR染料缀合物， 在这些体外分析中，将进一步在体内评价：1）肿瘤特异性，2）非肿瘤特异性， GMP毒性，3）生物稳定性，以及4）药代动力学和药效学。跟随示踪剂 将在切除腔的鼠模型中进行测试、安全性和有效性研究 映射以优化药剂的定时和剂量。 最终，这项工作将为这项技术在肺部的人体试验奠定基础。 鳞状细胞癌希望我们的联合开发创新对比 药物加上先进的术中器械将对 降低鳞状细胞肺癌术后局部和区域复发率。作为 作为第二个目的，这项研究将作为申请人的培训平台， 在肿瘤生物学，示踪剂设计，哺乳动物细胞技术，和小鼠的能力， 实验，以及为申请人提供指导，以实现成为一个 独立调查员

Project Summary Cancer continues to affect broad segments of the population, with over 600,000 deaths expected from malignancies this year in the United States.[1] Complete surgical resection, as compared to chemotherapy or radiation alone, offers nearly a nearly tenfold increase in the likelihood of cure for most solid tumors. However, local and systemic recurrence affect 40% of patients undergoing curative-intent resection, due to incomplete disease clearance and positive margins at the index operation.[2] To aid in the completeness of cancer resection—and thus improve patient survival—intraoperative molecular imaging (IMI) has been heralded as an important new tool in surgical oncology. The technology uses fluorescent, tumor-targeted tracers to identify positive margins and preoperatively unrecognized sites of disease. IMI has been applied to thoracic tumors in recent years.[3] However, there is a major unmet need in pulmonary squamous cell carcinoma, which is the second-most common lung cancer subtype and has a particularly low 5 year survival rate at 17.6%.[4] This is a translational proposal with the primary goal of developing and optimizing an optical molecular imaging probe for SCC. We aim to synthesize an EGFR-targeted near infrared (NIR) tracer that is specific to SCC and is biocompatible, using methods established in our lab and by close collaborators. The tracer will first be evaluated in vitro for: 1) receptor binding affinity, 2) nonspecific binding (competitive with excess unlabeled ligand), 3), water solubility, 4) serum protein binding, and 5) photo- and chemical stability. Targeted NIR dye conjugates that perform well in these in vitro analyses will be further evaluated in vivo for: 1) tumor specificity, 2) non- GMP toxicity, 3) biostability, and 4) pharmacokinetics and pharmacodynamics. Following tracer testing, safety and efficacy studies will be performed in a murine model of resection cavity mapping to optimize the timing and dose of the agent. Ultimately, this work will set the stage for human trials of this technology in pulmonary squamous cell carcinoma. We hope that the combined development of innovative contrast agents coupled with advanced intraoperative instrumentation will make a major impact in reducing the local and regional recurrence rates of squamous cell lung cancer after surgery. As a secondary aim, this research will serve as a training platform for the applicant towards competency in tumor biology, tracer design, mammalian cell techniques, and murine experiments, as well as provide the applicant with mentoring towards the goal of becoming an independent investigator.