Receptor-Targeted Fluorescence-Guided Surgery in Pancreatic Neuroendocrine Tumors

项目摘要 该提案的目标是临床上转化荧光标记的造影剂，其改善了外科手术 胰腺神经内分泌肿瘤（pNET）患者的预后。手术是主要的治疗选择， 这些患者，如果肿瘤被完全切除，可以治愈。然而，无法准确识别 术中pNET可导致次优手术结局和生存率降低。荧光引导 外科手术（FGS）可以潜在地解决这种临床需求，但缺乏分子靶向荧光 迄今为止，代理限制了其在pNET中的效用。因此，我们的团队将临床放射性示踪剂66 GaDOTA- TOC转化为荧光对应物，其在异种移植模型和手术模型中显示出高度选择性摄取。 表达生长抑素受体亚型2（SSTR 2）的生物标本。已知染料部分的一个关键缺点是 如IR 800，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。作为 结果，试剂摄取在非靶组织中是显著的，并导致降低的图像对比度。两性离子（即， 电荷平衡）染料已被开发以克服这一限制，并已超过IR 800 比较研究中的同行。为了评估染料电荷对体内性能的影响，我们替换了 IR 800与电荷平衡近红外荧光染料FNIR-Tag，产生第二代 代理，MMC（FNIR-标签）-TOC。我们的初步数据表明，MMC（FNIR-Tag）-TOC具有显著降低 背景信号比第一代试剂在几乎所有正常组织中沿着更高的肿瘤摄取。 肿瘤与背景比值的显著增加表明了术中检测的巨大潜力 表达SSTR 2的肿瘤和高翻译效用，如在表达SSTR 2的患者来源的 在异种移植（PDX）肿瘤模型和原位肿瘤模型中显示出极好的相关性 术前核成像、FGS和组织病理学之间的关系。我们还展示了安全性的初步证据 并确定了支持药剂规模扩大的制造工艺。我们力求在这些发现的基础上 并提出以下具体目标：（1）实施一项制造计划，以支持IND赋能研究， (2)检查临床前毒性/药理学，并完成所需的文件，以提交 IND申请，以及（3）在pNET患者中进行首次人体I期临床研究。完成 我们的目标，我们已经形成了一个强大的研究团队，结合博士的专业知识。 Pl）在造影剂开发方面与lkoma博士（多Pl）在外科肿瘤学方面的专业知识相结合。该团队正在 由MD安德森癌症中心的外科医生支持，该中心专门治疗NET和医疗 负责监督世界上最大的NET中心之一的肿瘤学家。成功完成我们的目标， 证明2/3期研究的可行性，以评估我们的策略的有效性，并将广泛影响 通过作为开发适合于手术引导的其他靶向剂的模型，

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.