Intraoperative Molecular Imaging of Pulmonary Squamous Cell Carcinoma

项目摘要 癌症继续影响着广大人口，有60多万人死于癌症 预计今年美国的恶性肿瘤。[1]完全手术切除，如 与单纯的化疗或放射治疗相比， 治愈大多数实体肿瘤的可能性。然而，局部和全身性复发影响40% 因疾病清除不完全和阳性而接受根治性切除的患者 索引操作的边缘。[2]以帮助癌症切除的完整性--因此 提高患者存活率-术中分子成像(IMI)已被认为是一种 外科肿瘤学的重要新工具。这项技术使用了针对肿瘤的荧光 示踪剂，以确定阳性切缘和术前未识别的疾病部位。IMI有 近年来应用于胸部肿瘤。[3]然而，有一个主要的需求尚未得到满足 肺鳞状细胞癌是第二常见的肺癌亚型 而且5年存活率特别低，只有17.6%。 这是一份翻译建议书，主要目标是开发和优化光纤 鳞状细胞癌的分子成像探针。我们的目标是合成一种EGFR靶向的近红外(NIR) 使用我们实验室建立的方法和通过 亲密的合作者。示踪剂将首先在体外进行评估：1)受体结合亲和力，2) 非特异性结合(与多余的未标记配体竞争)，3)，水溶性，4)血清 蛋白质结合，以及5)光和化学稳定性。靶向近红外染料偶联物 在这些体外分析中，将进一步在体内评估：1)肿瘤特异性，2)非 GMP毒性，3)生物稳定性，4)药代动力学和药效学。跟踪示踪剂 测试、安全性和有效性研究将在切除空洞的小鼠模型中进行 映射以优化试剂的时间和剂量。 最终，这项工作将为这项技术在肺部进行人体试验奠定基础。 鳞状细胞癌。我们希望结合发展，形成创新对比 药物与先进的术中器械相结合将对 降低鳞状细胞肺癌术后局部和区域复发率。AS 作为次要目标，这项研究将作为申请者的培训平台 精通肿瘤生物学、示踪剂设计、哺乳动物细胞技术和小鼠 实验，以及为申请者提供指导，朝着成为一名 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.