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）是一种侵袭性恶性肿瘤，手术切除是最有效的治疗方法 选项。对强光可视化和触觉提示的依赖限制了 PC 和 PC 手术切除的效率 其癌前前驱病变并导致不良结果。术中荧光引导 提高分期以及肿瘤手术的准确性，并降低局部复发率 并提高了生存率。荧光引导成像的成功取决于灵敏度和 用于检测 PC 及其先兆病变的标记物的特异性。我们的多项研究 实验室和其他人已经确定了 MUC4 在胰腺病理中的差异表达。虽然它是 在正常胰腺中无法检测到，MUC4 的从头过度表达仅限于高风险前体 病变和侵袭性PC及其表达逐渐增加，疾病进展。一个内部 生成针对 MUC4、8G7 的单克隆抗体 (mAb)，该抗体可识别串联的重复表位 重复结构域，已成为超灵敏检测和定义 MUC4 在肿瘤中的作用的有用工具 进展和转移。 PC 中 MUC4 的高表达与生存率低相关，而前体细胞中 MUC4 的高表达与生存率低相关。 病变中，MUC4 表达是恶性风险的预测因子。我们的初步研究表明，系统地 施用用 NIRF 染料 IRDye800CW 标记的 mAb 8G7 可以非常灵敏地照亮表达 MUC4 的信号 体内皮下和原位肿瘤。此外，我们还开发了一种独特的动物模型 概括了 MUC4 驱动的 IPMN 到侵袭性 PC 的进展。在此模型中，胰腺特异性诱导 人类 MUC4 的表达与致癌的 KrasG12D 结合导致癌前病变的发展 IPMN 和 PanIN 病变进展为侵袭性 PC。该提案旨在开发和评估 MUC4- 用于 PC 及其癌前病变临床前光学手术导航的靶向 NIR 探头 模型。我们假设术中使用 MUC4 靶向近红外荧光 (NIRF) 成像探头将改善 PC 及其高危前驱病变的切除。为了测试这个 假设，提出了两个具体目标。目标 1 的研究重点是合成、表征和（预） MUC4 靶向近红外荧光缀合物的临床安全性分析。目标 2 研究评估 MUC4靶向成像探针在患者来源的原位异种移植（PDOX）模型中的临床前疗效， 人类MUC4转基因GEM模型和临床标本。总体而言，靶向成像的发展 探头可以改善前体病变和 PC 的检测和无切缘切除。研究 本申请中提出的将开发和测试针对 MUC4（顶级 PC 中差异过表达的膜粘蛋白）用于 PC 及其前驱病变的手术导航。 研究目标的成功实现将为迫切需要的一期临床试验铺平道路 用于改进 PC 及其高风险前驱病变的检测和手术切除的成像探头。