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.

项目总结 头颈部鳞状细胞癌(HNSCC)是第六大最常见的癌症类型，超过65万人 全世界每年确诊的病例。据报道，高达30%的头颈部癌症患者的切缘为正。 其中利润率状况是总体生存的主要预后因素。术前做X光检查时，计算 体层摄影术(CT)和超声成像使深度评估、诊断和外科计划成为可能， 术前影像与术中真实情况之间仍存在差距。准确的外科鉴定 对肿瘤边缘和小病变的评估仍然具有挑战性。令人惊讶的是，没有一种临床批准的技术可以 直接加强头颈部肿瘤切除和组织保护的术中指导， 这通常是通过解剖学知识、视觉提示和触诊来执行的。荧光导引 外科手术(FGS)已经成功地整合到临床医学中，只有两种FDA批准的近红外(NIR， 650-900 nm)荧光团。FGS系统几乎只在近红外区域工作，在那里组织染色- 佛尔吸光度、自体荧光和散射降至局部极小值，从而实现高对比度和高分辨率 成像深度可达一厘米。使用肿瘤特异性FGS的术中指导可以显著改善 头颈部癌症患者的手术结果，为外科手术提供了一个新的范例。一个重要的骗局- 临床广泛采用的选择是易于在目前的外科工作流程中实施。目前， 大多数正在开发的FGS造影剂被归类为“始终在线”探头，其中连续的 荧光发射发生在整个成像过程中，与探针与其结合目标的接近程度无关。关闭- 这些常开探头的靶标积累导致背景信号升高，并有相当大的量 需要时间来清除非特异性探针积聚以产生足够的肿瘤背靠背- 手术中用于决策的地面比(TBR)。患者被要求注射造影剂- 手术前几天。对于患者来说，这意味着额外的就诊费用和压力。这 部分是由于较大的探针尺寸导致有限的渗出、较长的循环时间和肿瘤受损。 穿透力。为了缓解这些挑战，具有高度特异性和亲和力的较小靶向部分是高度 希望在系统管理后不久即可提供卓越的TBR，允许随时集成到前 列出手术流程。在此，我们建议开发一种新的肿瘤靶向FGS解决方案来解决这一问题 未得到满足的临床需求。我们将开发一流的近红外荧光探针，针对Head中EGFR的突变 而宫颈癌，其中高TBR将对准确的肿瘤边缘评估、小肿瘤的检测至关重要 肿瘤结节、残留病变和多灶性病变。这些新的荧光探针作为术中辅助 能够以高灵敏度和高特异性实时识别和区分这些肿瘤，可以标志着 显著降低头颈部癌患者的切缘阳性率并改善手术结果。