Receptor-Targeted Fluorescence-Guided Surgery in Pancreatic Neuroendocrine Tumors

项目总结 这项提议的目标是在临床上翻译一种荧光标记的造影剂，以改善外科手术。 胰腺神经内分泌肿瘤(PNETs)患者的预后手术是治疗该病的主要选择 如果肿瘤被完全切除，这些患者是可以治愈的。然而，无法准确识别 术中PNETs可导致不理想的手术结果并降低存活率。荧光导引 手术(FGS)可以潜在地解决这一临床需求，但缺乏分子靶向的荧光 到目前为止，代理在PNETS中的应用受到了限制。因此，我们的团队将临床放射性示踪剂66GaDOTA- TOC，转化为在异种移植模型和外科手术中显示高度选择性摄取的荧光对应物 表达生长抑素受体亚型2(SSTR2)的生物样本。众所周知，染料部分的一个主要缺点是 作为IR800，是它的高度负电荷，导致与血清蛋白和组织的非特异性相互作用。AS 结果，试剂摄取在非靶组织中显著，并导致图像对比度降低。两性离子(即， 电荷平衡)染料是为了克服这一限制而开发的，其性能超过了IR800 比较研究中的对应者。为了评估染料电荷对体内性能的影响，我们用 IR800与电荷平衡的近红外荧光染料FNIR-TAG，生产第二代 代理，MMC(fnir-tag)-TOC我们的初步数据显示，MMC(FNIR-TAG)-TOC显著低于 背景信号比第一代试剂在几乎所有正常组织中都具有更高的肿瘤摄取率。 肿瘤与本底比值的显著增加暗示了术中检测的良好潜力。 在一个表达SSTR2的患者来源的肿瘤中发现表达SSTR2的肿瘤和高翻译效用 异种移植(PDX)肿瘤模型和显示出良好相关性的原位肿瘤模型 术前核成像、FGS和组织病理学之间的关系。我们还展示了安全的初步证据 并确定了一种支持试剂放大的制造工艺。我们寻求在这些调查结果的基础上 并提出以下具体目标：(1)实施制造计划，以支持支持IND的研究， (2)检查临床前毒性/药理学，并填写所需文件以提交 IND应用，以及(3)在PNETs患者中进行首个人类阶段1临床研究。要完成 为了实现我们的目标，我们组建了一支强大的调查团队，结合了Azhdarinia博士(联系人)的专业知识 与Ikoma博士(多PL)在外科肿瘤学方面的专业知识形成对比的是药物开发。这个团队是 由MD安德森癌症中心的外科医生支持，该中心专门治疗Net和 负责监管世界上数量最多的网络中心之一的肿瘤学家。成功完成我们的目标将 论证2/3阶段研究的可行性，以评估我们战略的有效性，并将广泛影响 作为开发适用于外科手术指导的其他靶向制剂的模型，该技术在该领域具有广泛的应用前景。

PROJECT SUMMARY The goal of this proposal is to clinically translate a fluorescently labeled contrast agent that improves surgical outcomes in patients with pancreatic neuroendocrine tumors (pNETs). Surgery is the main treatment option for these patients and can be curative if tumors are completely removed. However, the inability to accurately identify pNETs intraoperatively can lead to sub-optimal surgical outcomes and decreased survival. Fluorescence-guided surgery (FGS) could potentially address this clinical need, but the absence of a molecularly targeted fluorescent agent has thus far limited its utility in pNETs. Accordingly, our team converted the clinical radiotracer, 66GaDOTA- TOC, into a fluorescent counterpart that showed highly selective uptake in xenograft models and surgical biospecimens that express somatostatin receptor subtype 2 (SSTR2). A key drawback of the dye moiety, known as IR800, is its highly negative charge that leads to non-specific interaction with serum proteins and tissues. As a result, agent uptake is significant in non-target tissues and leads to reduced image contrast. Zwitterionic (i.e., charge-balanced) dyes have been developed to overcome this limitation and have outperformed IR800 counterparts in comparative studies. To evaluate the effects of dye charge on in vivo performance, we replaced IR800 with the charge-balanced near-infrared fluorescent dye, FNIR-Tag, to produce the second-generation agent, MMC(FNIR-Tag)-TOC. Our preliminary data showed that MMC(FNIR-Tag)-TOC had significantly lower background signal than the first-generation agent in nearly all normal tissues along with higher tumor uptake. The remarkable increase in tumor-to-background ratios suggests excellent potential for intraoperative detection of SSTR2-expressing tumors and high translational utility as demonstrated in an SSTR2-expressing patient-derived xenograft (PDX) tumor model and in an orthotopic tumor model that showed excellent correlation between preoperative nuclear imaging, FGS, and histopathology. We also showed preliminary evidence of safety in mice and identified a manufacturing process to support agent scale-up. We seek to build on these findings and propose the following specific aims: (1) implement a manufacturing plan to support IND-enabling studies, (2) examine preclinical toxicity/pharmacology and complete the required documentation for submission of an IND application, and (3) conduct a first-in-human phase 1 clinical study in patients with pNETs. To accomplish our aims, we have formed a strong investigational team that combines the expertise of Dr. Azhdarinia (contact Pl) in contrast agent development with the expertise of Dr. lkoma (multi-Pl) in surgical oncology. The team is supported by surgeons from MD Anderson Cancer Center that specialize in treating NETs and medical oncologists who oversee one of the world's highest-volume NET centers. Successful completion of our aims will demonstrate feasibility for phase 2/3 studies to evaluate the efficacy of our strategy and will broadly impact the field by serving as a model for the development of other targeted agents that are suitable for surgical guidance.