Molecular Imaging Probe(s) for Optical Surgical Navigation of Pancreatic Cancer

用于胰腺癌光学手术导航的分子成像探针

• 批准号: 10367553
• 负责人: Surinder K. Batra
• 金额: $ 46.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10367553
• 关键词: Adenocarcinoma; American; Animal Model; Autopsy; Biodistribution; Cancer Detection; Cancer Etiology; Cell Line; Cessation of life; Chemotherapy and/or radiation; Clinical; Consensus; Cues; Cystic Lesion; Detection; Development; Diagnostic; Disease; Disease Progression; Drug Kinetics; Dyes; Epitopes; Excision; Exhibits; Fine needle aspiration biopsy; Fluorescence; Fluorescent Dyes; Fluorescent Probes; Genetically Engineered Mouse; Goals; Human; Image; Image-Guided Surgery; KRASG12D; Label; Laboratories; Laparoscopy; Lesion; Light; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of pancreas; Membrane; Modality; Modeling; Molecular Weight; Monoclonal Antibodies; Mucins; Nature; Near-Infrared Fluorescence Imaging Probe; Neoplasm Metastasis; Oncogenic; Operative Surgical Procedures; Optics; Outcome; Pancreas; Pancreatic Adenocarcinoma; Pancreatic Intraepithelial Neoplasia; Pathology; Patients; Performance; Phase I Clinical Trials; Pre-Clinical Model; Progressive Disease; Recurrence; Resistance; Risk; Role; Sampling; Sensitivity and Specificity; Signal Transduction; Societies; Specificity; Specimen; Staging; Surgical Oncology; Survival Rate; Tactile; Tandem Repeat Sequences; Testing; Time; Tissues; Toxic effect; Transgenes; Transgenic Organisms; Tumor Tissue; Visualization; Xenograft Model; antibody conjugate; base; cancer invasiveness; clinical efficacy; differential expression; ex vivo imaging; fluorescence imaging; high risk; image guided; imaging modality; imaging probe; improved; in vivo; inducible gene expression; molecular imaging; mouse model; overexpression; pancreatic neoplasm; pre-clinical; pre-clinical assessment; preclinical efficacy; preclinical evaluation; preclinical safety; preclinical study; premalignant; programs; subcutaneous; success; targeted imaging; tool; tumor; tumor progression

ABSTRACT Pancreatic cancer (PC) is an aggressive malignancy where surgical resection is the most effective curative option. Reliance on bright light visualization and tactile cues limit the efficiency of surgical resection for PC and its premalignant precursor lesions and contribute to unfavorable outcomes. Intraoperative fluorescence guidance improves both stagings as well as the accuracy of oncologic surgeries and results in lower local recurrence rates and improved survival. The success of fluorescence-guided imaging is dependent on the sensitivity and specificity of a marker being utilized for detecting PC and its precursor lesions. Multiple studies from our laboratory and others have established the differential expression of MUC4 in pancreatic pathologies. While it is undetectable in the normal pancreas, de novo overexpression of MUC4 is restricted to high-risk-precursor lesions and invasive PC and its expression increases progressively disease advancement. An in-house generated monoclonal antibody (mAb) against MUC4, 8G7, which recognizes repetitive epitopes in the tandem repeat domain, has emerged as a useful tool for ultrasensitive detection and defining the role of MUC4 in tumor progression and metastasis. High MUC4 expression in PC is associated with poor survival, while in precursor lesions, MUC4 expression is a predictor of malignant risk. Our preliminary studies indicate that systemically administered mAb 8G7 labeled with NIRF dye IRDye800CW can very sensitively illuminate MUC4-expressing subcutaneous and orthotopic tumors in vivo. Further, we have developed a unique animal model that recapitulates MUC4-driven IPMN-to-invasive PC progression. In this model, pancreas-specific inducible expression of human MUC4 in conjunction with oncogenic KrasG12D results in the development of premalignant IPMN and PanIN lesions that progress to invasive PC. The proposal seeks to develop and evaluate MUC4- targeted NIR probes for optical surgical navigation of PC and its premalignant precursor lesions in the preclinical models. We hypothesize that intraoperative use of MUC4-targeted Near-Infrared Fluorescent (NIRF) imaging probes will improve the resection of PC and its high-risk precursor lesions. To test this hypothesis, two specific aims are proposed. Studies in Aim 1 focus on the synthesis, characterization, and (pre) clinical safety profiling of MUC4-targeted near-infrared fluorescent conjugates. Aim 2 studies evaluate the preclinical efficacy of MUC4-targeted imaging probes in patient-derived orthotopic xenograft (PDOX) models, human MUC4 transgenic GEM models, and clinical specimens. Overall, the development of targeted imaging probes can improve both the detection and margin-free resection of precursor lesions and PC. The studies proposed in this application will develop and test high-performance NIR probes targeting MUC4 (a top differentially overexpressed membrane mucin in PC) for surgical navigation in PC and its precursor lesions. Successful accomplishment of study goals will pave the path for a Phase I clinical trial for urgently needed imaging probes for improved detection and surgical resection of PC and its high-risk precursor lesions.

抽象的 胰腺癌（PC）是一种侵略性恶性肿瘤，手术切除是最有效的治愈性 选项。依赖明亮的光线可视化和触觉提示限制了PC和PC的手术切除效率 它的前体病变，并导致不利的结果。术中荧光引导 提高停滞和肿瘤手术的准确性，并导致局部复发率较低 并改善了生存。荧光引导成像的成功取决于灵敏度和 用于检测PC及其前体病变的标记的特异性。来自我们的多项研究 实验室和其他人在胰腺病理中确定了MUC4的差异表达。虽然是 在正常胰腺中无法检测到的MUC4的从头表达仅限于高风险的人 病变和侵入性PC及其表达增加了逐渐疾病的进步。内部 对MUC4，8G7产生的单克隆抗体（MAB），该抗体识别串联中的重复表位 重复域已成为超敏检测并定义MUC4在肿瘤中的作用的有用工具 进展和转移。 PC中高的MUC4表达与存活不良有关，而在前体中 病变，MUC4表达是恶性风险的预测指标。我们的初步研究表明 用NIRF DYE IRDYE800CW标记的MAB 8G7可以非常敏感地照亮MUC4表达 体内皮下和原位肿瘤。此外，我们开发了一种独特的动物模型 概括了MUC4驱动的IPMN至侵入性PC进程。在此模型中，胰腺特异性诱导 人类MUC4与致癌KRASG12D结合的表达导致了先决性的发展 IPMN和PANIN病变会发展为侵入性PC。该提案旨在开发和评估MUC4- 针对PC的光学手术导航及其临床前病变的靶向NIR探针 型号。我们假设术中使用MUC4靶向的近红外荧光（NIRF） 成像探针将改善PC的切除及其高风险前体病变。测试这个 假设，提出了两个具体目标。 AIM 1的研究专注于合成，表征和（PRE） MUC4靶向近红外荧光偶联物的临床安全分析。 AIM 2研究评估 MUC4靶向成像探针在患者衍生的原位异种移植（PDOX）模型中的临床前功效， 人MUC4转基因宝石模型和临床标本。总体而言，目标成像的发展 探针可以改善前体病变和PC的无检测和边缘切除。研究 在本应用程序中提出的将开发和测试针对MUC4的高性能NIR探针（顶部 PC中差异表达过表达的膜粘蛋白）用于PC及其前体病变中的手术导航。 成功实现学习目标将为急需的I期临床试验铺平道路 成像探针改善了PC及其高风险前体病变的检测和手术切除术。