Near-infrared Choline Kinase Sensors for Intraoperative Identification of Lung Tumor Margins

项目总结 肿瘤手术后最重要的预后指标是完全切除。术中 肿瘤边缘的检测具有挑战性，残留疾病仍然是最常见的原因 局部复发。完全切除可延长患者生存时间并改善术后质量。 生活。使用具有靶向荧光团的近红外(NIR)成像对肿瘤的视觉增强可以识别 肉眼观察或触诊不能发现的病变。近红外成像提供高分辨率和 灵敏度高，可在术中环境下实时进行。 这项应用旨在测试靶向近红外荧光团在小鼠肿瘤模型中的检测效果。 并将这些发现转化为指导术中犬患者手术切除肿瘤的方法 患有自发性肺癌。肺癌是与癌症相关的主要死亡原因，也是第三大致死原因。 在美国被诊断出癌症。在非小细胞肺癌(NSCLC)中，占90% 临床肺癌中，肿瘤切除仍然是治疗局部肺癌患者最有效的方法 疾病。外科医生通常使用肉眼检查和手指触诊来确定实体肿瘤的边缘。 然而，这种方法往往不足以检测残留病，从而导致局部区域 在这个队列中，高达40%的患者复发，显著降低了5年生存率。 在这项提议中，我们将使用我们实验室合成的用于检测胆碱激酶的近红外探针 (CHOK)，一种在肿瘤发生早期上调的脂蛋白激酶，在56%的肺癌中过表达，甚至在 83%的非小细胞肺癌。这些探针将在两个模型的NSCLC中测试它们检测肿瘤边缘的能力 老鼠。我们将评估荧光素靶向和非荧光素治疗后小鼠肿瘤复发和存活的时间 有针对性的手术切除。从这些数据中，将选择一个荧光团用于GLP合成 在一群犬类中评估其条件和全身毒性。然后我们将招募一个30人的患者队列 向宾夕法尼亚大学兽医学院赠送患有自发非小细胞肺癌的同伴动物。 我们的初步研究表明，犬非小细胞肺癌显著过度表达Chok，这种表达是 在整个肿瘤中是均匀的。我们将使用术中近红外荧光引导手术，使用我们的 用于检测肿瘤和识别肿瘤边缘的CHOK探针。犬只切除后恢复， 随着时间的推移，患者将接受肿瘤复发和患者生存的监测。这些数据将与 使用非靶向荧光团切除肿瘤的阳性和阴性对照队列 吲哚青绿(ICG)或在近红外荧光引导下切除。这些研究将测试 我们的Chok传感器在犬自发性肺癌中检测肿瘤边缘的能力 病人队列。我们的长期目标是开发用于术中实时手术的靶向近红外荧光团 在人类癌症患者身上。

PROJECT SUMMARY The most important prognostic indicator following cancer surgery is complete resection. Intraoperative detection of tumor margins is challenging, and residual disease continues to be the most common cause of local recurrence. Complete resection results in prolonged patient survival and improved post-surgical quality of life. Visual enhancement of tumors using near-infrared (NIR) imaging with targeted fluorophores can identify lesions that are not detectable by visual observation or palpation. NIR imaging offers high resolution and sensitivity and can be performed in real time in an intraoperative setting. This application aims to test the efficacy of targeted NIR fluorophores for tumor detection in murine models of lung cancer and to translate these findings to guide intraoperative surgical tumor removal in canine patients with spontaneous lung cancer. Lung cancer is the leading cancer-related cause of death and the third most diagnosed cancer in the United States. In non-small cell lung carcinomas (NSCLC), which represent 90% of clinical lung cancers, tumor resection continues to be the most effective approach to cure patients with local disease. Surgeons typically use visual inspection and finger palpation to define solid tumor margins. However, this approach is often insufficient for the detection of residual disease, thus leading to locoregional recurrence in up to 40% of patients and significantly reduced 5-year survival in this cohort. In this proposal, we will use NIR probes synthesized in our laboratory and designed to detect choline kinase (ChoK), a lipid kinase upregulated early in tumorigenesis and overexpressed in 56% of lung cancers and up to 83% of NSCLC. These probes will be tested for their ability to detect tumor margins in two models of NSCLC in mice. We will evaluate time to tumor recurrence and survival in mice after fluorophore-targeted and non- targeted surgical excision. From these data, one fluorophore will be selected for synthesis under GLP conditions and its systemic toxicity evaluated in a cohort of canines. We will then recruit a patient cohort of 30 companion animals presenting to the University of Pennsylvania Veterinary School with spontaneous NSCLC. Our Preliminary Studies indicate that canine NSCLC significantly overexpress ChoK and that this expression is homogeneous throughout the tumor. We will employ intraoperative NIR fluorescence-guided surgery using our ChoK probes for detection of tumors and identification of tumor margins. After resection and recovery, canine patients will be monitored over time for tumor recurrence and patient survival. These data will be compared to positive and negative control cohorts where tumors were resected using the non-targeted fluorophore indocyanine green (ICG) or resected without the aid of NIR fluorescence guidance. These studies will test the ability of our ChoK sensors to detect tumor margins in spontaneously occurring lung cancers in a canine patient cohort. Our long-term goal is to develop targeted NIR fluorophores for real time intraoperative surgery in human cancer patients.