Translating phospholipase activatable fluorophores for the sensitive detection of non-small cell lung cancer

翻译磷脂酶可激活荧光团以灵敏检测非小细胞肺癌

• 批准号: 10579984
• 负责人: EDWARD J DELIKATNY
• 金额: $ 46.08万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579984
• 关键词: Adopted; Animals; Arachidonic Acids; Autopsy; Back; Biochemistry; Biodistribution; Cancer Detection; Cancer Patient; Canis familiaris; Cause of Death; Cells; Chemotherapy and/or radiation; Client; Clinical; Clinical Trials; Companions; Complete Blood Count; Contractor; Data; Deposition; Detection; Development; Disease; Drug Kinetics; Enzymes; Esterification; Excision; Exhibits; Failure; Fingers; Fluorescence; Fluorescent Probes; Formulation; Goals; Histology; Human; Image; Image-Guided Surgery; Indocyanine Green; Injections; Institution; Investigational New Drug Application; Kinetics; Lesion; Leukotrienes; Liposomes; Lung; Lung Adenocarcinoma; Lung Neoplasms; Lymph Node Dissections; Malignant Neoplasms; Malignant neoplasm of lung; Maximum Tolerated Dose; Measures; Mus; Near-infrared optical imaging; Neoplasm Metastasis; Non-Small-Cell Lung Carcinoma; Nonmetastatic; Operative Surgical Procedures; Organ; Palpation; Pathway interactions; Patients; Periodicity; Phospholipase; Primary Neoplasm; Prostaglandins; Quality of life; Radiation therapy; Recurrence; Recurrent tumor; Residual Neoplasm; Resolution; Safety; Sensitivity and Specificity; Serum; Signal Transduction; Solid Neoplasm; Staging; Surgeon; Survival Rate; Testing; Time; Topical application; Toxic effect; Toxicology; Tracer; Translating; Translations; Tumor Tissue; United States; Urinalysis; Veterinary Schools; Visual; Work; arachidonate; cancer cell; cancer diagnosis; cancer surgery; clinical translation; cohort; companion animal; comparison control; contrast enhanced; design; detection sensitivity; dodecyldimethylamine oxide; draining lymph node; fluorescence-guided surgery; fluorophore; folate-binding protein; good laboratory practice; hydroxyl group; imaging agent; improved; improved outcome; in vivo; liposomal formulation; lung Carcinoma; lymph nodes; millimeter; mouse model; neoplastic cell; novel; operation; overexpression; prognostic indicator; recruit; relapse patients; response; restoration; scale up; surgery outcome; systemic toxicity; tumor; tumorigenesis; wound bed

PROJECT SUMMARY This application proposes to translate activatable fluorophores targeted to cytosolic phospholipase A2α (cPLA2α) for intraoperative surgical detection in lung cancer. Lung cancer is the leading cancer-related cause of death and the third most diagnosed cancer in the United States. Non-small cell lung carcinomas (NSCLC), represent 90% of lung cancers, and surgical resection continues to be the most effective approach to cure patients with low stage premetastatic disease. Surgeons typically use visual inspection and finger palpation to define solid tumor margins. However, this approach is often insufficient to detect residual disease, leading to recurrence in up to 40% of patients and significantly reduced 5-year survival. Improving intraoperative detection of tumor margins is imperative, because small foci of residual disease at or close to the resection margins are the most common cause of local recurrence. The most important prognostic indicator following cancer surgery is complete resection, which prolongs patient survival and improves post- surgical quality of life. Contrast enhancement of tumors using near-infrared (NIR) imaging with targeted fluorophores can identify small lesions that are not detectable by visual observation or palpation. NIR imaging offers high resolution and sensitivity and can be performed in real-time during surgery. In this application, we propose to translate DDAO-arachidonate (DDAO-A), an activatable probe designed to specifically target cPLA2α, a critical signaling enzyme upregulated early in tumorigenesis and overexpressed in more than 47% of NSCLC. Preliminary Studies indicate that DDAO-A is selectively activated by murine and human NSCLC tumors, and can detect small foci in both mouse models and excised human lung tumor tissue. DDAO-A will be synthesized under GLP conditions and dispersed in clinically approved liposomal formulations for delivery. Selected mouse studies will be performed to confirm probe activation, tumor targeting and the ability to detect tumor margins. Systemic toxicity will be evaluated in mice and in a small cohort of canines. We will utilize an established platform for clinical translation of NIR fluorophores, employing a canine clinical trial for intraoperative surgery. We will recruit a patient cohort of 30 companion animals with spontaneous NSCLC presenting to our Veterinary School. DDAO-A will be used for detection of primary tumors and identification of tumor margins during intraoperative fluorescence-guided surgery (FGS) in canine patients. We will investigate both systemic injection and topical application for detection of residual tumor. These data will be compared to control surgical cohorts using the non-targeted indocyanine green (ICG) or without NIR fluorescence guidance. If successful, this study will improve surgical outcomes by improving localization of small tumor deposits in the lung, lymph nodes and margins. The completion of these studies will form the basis for an investigational new drug (IND) application in support of a clinical trial to assess DDAO-A-guided surgery in human lung cancer patients.

项目概要 该申请建议翻译针对胞质磷脂酶 A2α 的可激活荧光团 (cPLA2α) 用于肺癌术中手术检测 肺癌是主要的癌症相关原因。 死亡人数和美国第三大诊断癌症。 90%的肺癌代表，手术切除仍然是最有效的治愈方法 患有低期转移前疾病的患者，外科医生通常使用目视检查和手指触诊来诊断。 然而，这种方法通常不足以检测残留病灶，从而导致 高达 40% 的患者复发并显着降低 5 年生存率。 改善肿瘤边缘的术中检测势在必行，因为在或 靠近切除边缘是局部复发的最常见原因，也是最重要的预后因素。 癌症手术后的指标是完全切除，这可以延长患者的生存期并改善术后效果 使用有针对性的近红外 (NIR) 成像增强肿瘤的手术生活质量。 荧光团可以识别肉眼观察或近红外成像无法检测到的小病变。 提供高分辨率和灵敏度，并且可以在手术过程中实时执行。 在此应用中，我们建议翻译 DDAO-花生四烯酸 (DDAO-A)，这是一种可激活探针，旨在 特异性靶向 cPLA2α，这是一种在肿瘤发生早期上调并过度表达的关键信号酶 初步研究表明，DDAO-A 在超过 47% 的 NSCLC 中被小鼠选择性激活。 人类非小细胞肺癌肿瘤，并且可以检测小鼠模型和切除的人类肺肿瘤组织中的小病灶。 DDAO-A将在GLP条件下合成并分散在临床批准的脂质体制剂中 将进行选定的小鼠研究以确认探针激活、肿瘤靶向和 我们将在小鼠和一小群犬科动物中评估检测肿瘤边缘的能力。 将利用已建立的平台进行近红外荧光团的临床转化，并进行犬类临床试验 我们将招募 30 只患有自发性 NSCLC 的伴侣动物进行术中手术。 向我们的兽医学校介绍。 DDAO-A将用于术中原发肿瘤的检测和肿瘤边缘的识别 我们将研究犬患者的荧光引导手术（FGS）。 检测残留肿瘤的应用程序将使用这些数据与对照手术队列进行比较。 非靶向吲哚菁绿 (ICG) 或无近红外荧光指导 如果成功，本研究将。 通过改善肺、淋巴结和淋巴结中小肿瘤沉积物的定位来改善手术结果 这些研究的完成将构成研究性新药（IND）申请的基础。 支持评估 DDAO-A 引导的人类肺癌患者手术的临床试验。