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: 10654865
• 负责人: Ali Azhdarinia
• 金额: $ 62.82万
• 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/10654865
• 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; Intraoperative Complications; Investigational Drugs; Investigational New Drug Application; Islet Cell Tumor; Label; Malignant neoplasm of ovary; Manufacturer; 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; Play; Postoperative Period; Pre-Clinical Model; Preparation; Procedures; Production; Property; Public Health; Quality of life; Rattus; Recurrent tumor; Research; Role; Safety; Serum; Serum Proteins; Signal Transduction; Small Intestines; Solid; Somatostatin Receptor; Specialized Center; Specific qualifier value; Stains; Surgeon; Surgical Oncology; Surgical margins; Synthesis Chemistry; Systemic Therapy; Tactile; Testing; Tissues; Toxicology; Translating; Visualization; Work; Xenograft Model; analog; cancer therapy; contrast imaging; cyanine; design; detection sensitivity; efficacy evaluation; first-in-human; fluorescence-guided surgery; fluorophore; good laboratory practice; imaging agent; imaging approach; imaging modality; improved; in vivo; innovation; manufacture; 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.

项目摘要 该建议的目的是在临床上翻译荧光标记的对比剂，以改善手术 胰腺神经内分泌肿瘤（PNETS）患者的结局。手术是主要治疗选择 这些患者，如果完全切除肿瘤，可以治愈。但是，无法准确识别 术中PNET可导致次优的外科手术结果和降低的存活率。荧光引导 手术（FGS）可能有可能满足这种临床需求，但缺乏分子靶向的荧光 到目前为止，代理商已限制了其在PNET中的效用。因此，我们的团队将临床放射性示踪剂转换为66gadota- TOC进入荧光对应物，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）的生物测量。染料部分的关键缺点，已知 作为IR800，其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，药物的摄取在非目标组织中是显着的，并导致图像对比度减少。 zwitterionic（即 已经开发了电荷平衡的染料来克服这一限制，并且表现优于IR800 比较研究中的对应物。为了评估染料电荷对体内性能的影响，我们替换了 IR800具有电荷均衡近红外荧光染料FNIR-TAG，以产生第二代 代理，MMC（FNIR-TAG）-toc。我们的初步数据表明，MMC（FNIR-TAG）-TOC显着降低 背景信号几乎与所有正常组织中的第一代药物以及较高的肿瘤吸收。 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的表达肿瘤和高转化实用性 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 在术前核成像，FG和组织病理学之间。我们还显示了安全的初步证据 在小鼠中，确定了一个制造过程以支持代理扩大规模。我们试图以这些发现为基础 并提出以下具体目的：（1）实施制造计划，以支持辅助研究， （2）检查临床前毒性/药理学，并完成提交所需的文档 IND应用，（3）对PNET患者进行了人类第一期临床研究。完成 我们的目标是，我们组成了一个强大的研究团队，结合了Azhdarinia博士的专业知识（联系 PL）与Lkoma博士（Multi-Pl）在外科肿瘤学中的专业知识相比发展。团队是 由MD安德森癌症中心的外科医生的支持，专门治疗网和医疗 监督世界上最多的净净中心之一的肿瘤学家。成功完成我们的目标将 证明了2/3阶段研究的可行性，以评估我们策略的功效，并将广泛影响 通过作为开发适合手术指导的其他靶向药物的模型来实现。

项目成果

Translational Potential of a Contrast Agent for FGS Applications in pNETs.

对比剂在 pNET 中 FGS 应用的转化潜力。

• DOI: 10.1007/s11307-024-01894-1
• 发表时间: 2024
• 期刊: Molecular imaging and biology
• 影响因子: 3.1
• 作者: AghaAmiri,Solmaz;Estrella,JeannelynS;Vargas,ServandoHernandez;Hurd,MarkW;Ghosh,SukhenC;Azhdarinia,Ali;Ikoma,Naruhiko
• 通讯作者: Ikoma,Naruhiko