Receptor-Targeted Fluorescence-Guided Surgery in Pancreatic Neuroendocrine Tumors

胰腺神经内分泌肿瘤受体靶向荧光引导手术

• 批准号: 10522096
• 负责人: Ali Azhdarinia
• 金额: $ 66.21万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10522096
• 关键词: Address; Back; Binding; Cancer Center; Canis familiaris; Caring; Cells; Charge; Chelating Agents; Clinic; Clinical; Clinical Research; Clinical Trials; Comparative Study; Consensus; Contracts; Contrast Media; Data; Detection; Development; Documentation; Dose; Drug Compounding; Drug Design; Dyes; Effectiveness; Excision; Exocrine pancreatic insufficiency; Feedback; Fluorescence; Fluorescent Dyes; Freeze Drying; Generations; Goals; Guidelines; Head and Neck Cancer; Histopathology; Human; Image; Image-Guided Surgery; Imaging technology; Impairment; Incidence; Injections; Investigation; Investigational Drugs; Investigational New Drug Application; Islet Cell Tumor; Label; Lead; Malignant neoplasm of ovary; Manufacturer Name; Mediating; Medical Oncologist; Metastatic Neoplasm to Lymph Nodes; Modeling; Molecular Target; Multifocal Lesion; Mus; Neoplasm Metastasis; Normal tissue morphology; Operating Rooms; Operative Surgical Procedures; Organ; Pancreatectomy; Patients; Penetration; Peptide Synthesis; Performance; Pharmacology; Pharmacology and Toxicology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Phase III Clinical Trials; Play; Postoperative Period; Pre-Clinical Model; Preparation; Procedures; Production; Property; Public Health; Quality of life; Rattus; Recurrence; Research; Role; Safety; Serum; Serum Proteins; Signal Transduction; Small Intestines; Solid; Somatostatin Receptor; Stains; Surgeon; Surgical Oncology; Surgical margins; Synthesis Chemistry; Systemic Therapy; Tactile; Testing; Tissues; Toxicology; Translating; Visualization; Work; Xenograft Model; analog; base; cancer therapy; contrast imaging; cyanine; design; detection sensitivity; efficacy evaluation; first-in-human; fluorescence-guided surgery; fluorophore; functional near infrared spectroscopy; good laboratory practice; imaging agent; imaging approach; imaging modality; improved; in vivo; innovation; manufacturing process; minimally invasive; model development; mortality risk; multimodality; novel; nuclear imaging; patient derived xenograft model; patient population; phase I trial; pre-clinical; preclinical safety; preclinical toxicity; primary endpoint; radiotracer; receptor; receptor binding; safety study; scale up; secondary endpoint; somatostatin analog; standard of care; surgery outcome; targeted agent; targeted imaging; theranostics; translational potential; tumor; tumor specificity; tumor xenograft; uptake

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.

项目概要 该提案的目标是在临床上转化一种荧光标记造影剂，以改善手术效果 胰腺神经内分泌肿瘤（pNET）患者的结果。手术是主要的治疗选择 这些患者如果完全切除肿瘤就可以治愈。但无法准确识别 术中使用 pNET 可能会导致手术结果不佳并降低生存率。荧光引导 手术（FGS）可能会解决这一临床需求，但缺乏分子靶向荧光 迄今为止，Agent 在 pNET 中的实用性有限。因此，我们的团队将临床放射性示踪剂 66GaDOTA- TOC 转化为荧光对应物，在异种移植模型和手术中显示出高度选择性的吸收 表达生长抑素受体亚型 2 (SSTR2) 的生物样本。已知染料部分的一个主要缺点 与 IR800 一样，其高负电荷会导致与血清蛋白和组织的非特异性相互作用。作为 因此，非目标组织中的药剂吸收量很大，并导致图像对比度降低。两性离子（即 电荷平衡）染料的开发克服了这一限制，并且性能优于 IR800 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 IR800 与电荷平衡近红外荧光染料 FNIR-Tag 一起生产第二代 剂，MMC（FNIR-标签）-TOC。我们的初步数据表明 MMC(FNIR-Tag)-TOC 显着降低 在几乎所有正常组织中，背景信号均优于第一代药物，并且肿瘤摄取更高。 肿瘤与背景比率的显着增加表明术中检测的巨大潜力 表达 SSTR2 的肿瘤和高翻译效用，如在表达 SSTR2 的患者来源中所证明的 异种移植 (PDX) 肿瘤模型和原位肿瘤模型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 在小鼠中进行实验，并确定了支持药物放大的制造工艺。我们寻求以这些发现为基础 并提出以下具体目标：(1) 实施制造计划以支持 IND 支持研究， (2) 检查临床前毒性/药理学并完成提交申请所需的文件 IND 申请，以及 (3) 在 pNET 患者中进行首次人体 1 期临床研究。为了完成 为了实现我们的目标，我们组建了一支强大的研究团队，结合了 Azhdarinia 博士的专业知识（联系方式 PL) 与 lkoma 博士 (multi-PL) 在外科肿瘤学方面的专业知识一起开发造影剂。该团队是 由 MD 安德森癌症中心的外科医生提供支持，专门治疗 NET 和医疗 负责监管世界上数量最多的 NET 中心之一的肿瘤学家。成功完成我们的目标将 证明 2/3 期研究的可行性，以评估我们策略的有效性，并将广泛影响 领域，作为开发其他适合手术指导的靶向药物的模型。