Small Molecule Probes for Fluorescence-guided Head and Neck Cancer Surgery

用于荧光引导头颈癌手术的小分子探针

• 批准号: 10644519
• 负责人: Lei Garrett Wang
• 金额: $ 19.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10644519
• 关键词: Address; Adopted; Adoption; Affinity; Anatomy; Antibodies; Behavior; Binding; Biological Markers; Circulation; Classification; Clinical; Clinical Medicine; Clinical Trials; Contrast Media; Cues; Decision Making; Detection; Development; Diagnosis; Disease; Drug Kinetics; Electron Transport; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Evaluation; Event; Excision; Extravasation; FDA approved; Fluorescence; Future; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Hospitals; Image; Impairment; Indocyanine Green; Injections; Knowledge; Label; Lesion; Ligands; Malignant Neoplasms; Methodology; Methylene blue; NMR Spectroscopy; Nodule; Operative Surgical Procedures; Optics; Outcome; Palpation; Patients; Penetration; Peptides; Pharmacodynamics; Postoperative Period; Prognostic Factor; Property; Reporting; Rodent; Sensitivity and Specificity; Signal Transduction; Specificity; Stress; Structure; System; Technology; Time; Tissue Preservation; Tissues; Translations; Ultrasonography; Validation; Visit; Visual; Work; X-Ray Computed Tomography; cancer surgery; cancer type; candidate selection; chromophore; clinical implementation; clinical practice; clinically relevant; cost; cytotoxicity; design; falls; fluorescence-guided surgery; fluorophore; head and neck cancer patient; high resolution imaging; improved; in vitro Assay; in vivo; inhibitor; lead candidate; liquid chromatography mass spectroscopy; molecular dynamics; mouse model; mutant; novel; pre-clinical; prevent; receptor binding; small molecule; surgery outcome; tumor; tumor specificity

PROJECT SUMMARY Head and neck squamous cell carcinoma (HNSCC) is the sixth most prevalent cancer type, with over 650,000 cases diagnosed annually worldwide. Positive margins are reported in up to 30% of head and neck cancer sur- geries, where margin status is a major prognostic factor for overall survival. While preoperative x-ray, computed tomography (CT) and ultrasound imaging have enabled in depth evaluation, diagnosis, and surgical planning, a gap continues to exists between preoperative imaging and intraoperative reality. Accurate surgical identification of the tumor margins and small lesions remains challenging. Surprisingly, no clinically approved technology can directly enhance intraoperative guidance for tumor resection and tis-sue preservation for head and neck cancers, which are typically performed through anatomical knowledge, visual cues and palpation. Fluorescence Guided Surgery (FGS) has successfully integrated into clinical medicine with only two FDA-approved near-infrared (NIR, 650-900 nm) fluorophores. FGS systems operate almost exclusively in the NIR region, where tissue chromo- phore absorbance, autofluorescence and scatter fall to local minima, permitting high contrast and high-resolution imaging at depths up to a centimeter. Intraoperative guidance with tumor-specific FGS could significantly improve surgical outcomes for head and neck cancer patients, providing a new paradigm for surgery. An important con- sideration for wide clinical adoption is ease of implementation into the current surgical workflow. Presently, the majority of FGS contrast agents under development are classified as “always-on” probes, where continuous fluorescence emission occurs throughout imaging, regardless of the probe proximity to its binding target. Off- target accumulation of these always-on probes leads to elevated background signal, and a considerable amount of time is required for the non-specific probe accumulation to be cleared to generate adequate tumor-to-back- ground ratio (TBR) for decision-making during the surgery. Patients are required to receive contrast agent injec- tion days before surgery. For patients, this implicates additional hospital visits with extra costs and stress. This is in part due to large probe size resulting in limited extravasation, long circulation times, and impaired tumor penetration. To alleviate these challenges, smaller targeting moieties with high specificity and affinity are highly desirable to provide superior TBR shortly after systemic administration, permitting ready integration into the ex- isting surgical workflow. Herein, we propose to develop a novel tumor-targeted FGS solution to address this unmet clinical need. We will develop first-in-class NIR fluorogenic probes that target mutants of EGFR in head and neck cancer, where high TBR will be crucial for accurate tumor margin assessment, the detection of small tumor nodules, residue lesions and multi-focal disease. These novel fluorogenic probes as intraoperative aid capable of identifying and distinguishing these tumors in real time with high sensitivity and specificity could sig- nificantly reduce positive margin rates and improve surgical outcomes for head and neck cancer patients.

项目摘要 头颈部鳞状细胞癌（HNSCC）是第六种最普遍的癌症类型，超过650,000 每年在全球诊断的病例。据报道，高达30％的头颈癌的阳性边缘表现出来 Geries，边缘状态是整体生存的主要原型因子。术前X射线，计算 断层扫描（CT）和超声成像已在深入评估，诊断和手术计划中启用 术前成像和术中现实之间的差距继续存在。准确的手术识别 肿瘤边缘和小病变仍然受到挑战。令人惊讶的是，没有临床认可的技术可以 直接增强肿瘤切除术的术中指导和头颈癌的Tis-Sue准备， 通常是通过解剖学知识，视觉提示和触诊来执行的。荧光指南 手术（FGS）已成功整合到临床医学中，只有两个FDA批准的近红外（NIR， 650-900 nm）荧光团。 FGS系统几乎完全在NIR区域运行，在此组织铬 凤凰吸收，自动荧光和散射掉落到局部最小值，允许高对比度和高分辨率 深度成像直至厘米。肿瘤特异性FG的术中指导可以显着改善 头颈癌患者的手术结局，为手术提供了新的范式。一个重要的骗局 用于广泛采用的辅助是在当前的手术工作流程中易于实施。目前， 大多数正在开发中正在开发的FGS对比剂被归类为“始终开”的问题，在此继续 荧光发射在整个成像过程中都会发生，而与其结合靶标的探针接近。离开- 这些始终遇到问题的目标积累会导致背景信号升高，并且考虑量 需要清除的非特异性探针积累需要时间才能产生足够的肿瘤到后背。 在手术过程中进行决策的地面比（TBR）。要求患者接受对比剂注射 - 手术前几天。对于患者，这意味着额外的医院就诊和额外的压力。这 部分原因是探针大小较大，导致渗出有限，循环长时间和肿瘤受损 渗透。为了减轻这些挑战，具有高特异性和亲和力的较小的针对部分是高度的 希望在系统给药后不久提供优质TBR，允许准备融入前 iSting手术工作流程。本文中，我们建议开发一种新型的肿瘤靶向FGS解决方案来解决这个问题 未满足的临床需求。我们将开发一流的NIR荧光问题，以靶向EGFR的头部突变体 和颈部癌，高TBR对于准确的肿瘤边缘评估至关重要，检测小 肿瘤结节，保留病变和多焦点疾病。这些新型的氟化问题是术中辅助 能够以高灵敏度和特异性实时识别和区分这些肿瘤 大幅度降低边缘率并改善头颈癌患者的手术结局。