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

摘要 胰腺癌是一种侵袭性的恶性肿瘤，手术切除是最有效的治疗方法。 选择。对强光可视化和触觉提示的依赖限制了PC和PC的手术切除效率 它是癌前病变的前驱病变，导致不良预后。术中荧光引导 改善分期和肿瘤手术的准确性，降低局部复发率 并提高了存活率。荧光引导成像的成功依赖于灵敏度和 用于检测前列腺癌及其前驱病变的标记物的特异性。来自我们的多项研究 实验室和其他人已经确定MUC4在胰腺病理中的差异表达。虽然它是 在正常胰腺中检测不到MUC4的从头表达仅限于高危前体 病变和侵袭性PC及其表达逐渐增加疾病进展。一个内部的 产生抗MUC4、8G7的单抗，识别串联中的重复表位 重复结构域，已成为超灵敏检测和确定MUC4在肿瘤中的作用的有用工具 进展和转移。在PC中高表达MUC4与生存不良有关，而在前体中则高表达MUC4 病变中，MUC4的表达是恶性风险的预测指标。我们的初步研究表明，从系统上讲 用NIRF染料IRDye800CW标记的单抗8G7可非常灵敏地照亮MUC4的表达 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到侵入性PC的进展。在这个模型中，胰腺特异的诱导 人MUC4与致癌基因KrasG12D联合表达导致癌前病变的发生 IPMN和Panin病变进展为侵袭性PC。该提案旨在开发和评估MUC4- 靶向近红外探头在临床前前列腺癌及其癌前病变光学手术导航中的应用 模特们。我们假设术中使用MUC4靶向的近红外荧光(NIRF) 影像探头有助于提高PC及其高危前驱病变的切除率。为了测试这一点 假设，提出了两个具体目标。目标1的研究集中在合成、表征和(Pre)。 以MUC4为靶标的近红外荧光结合物的临床安全性分析。目的2研究评估 MUC4靶向成像探针在患者来源的原位异种移植模型中的临床前疗效 人MUC4转基因GEM模型及临床标本。总体而言，靶向成像的发展 探头可提高先期病变和前列腺癌的检出和无切缘切除。这些研究 此应用程序中提议的将开发和测试针对MUC4(顶级 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急需的I期临床试验铺平道路 用于改进PC及其高危前驱病变的检测和手术切除的成像探头。

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.