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.

项目总结