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）是第六大最常见的癌症类型， 全球每年确诊的病例。据报道，在高达30%的头颈癌手术中， 边缘状态是总生存率的主要预后因素。术前X线、计算机 断层扫描（CT）和超声成像使深度评估，诊断和手术计划成为可能， 在术前成像和术中现实之间仍然存在差距。准确的手术识别 肿瘤边缘和小病灶的切除仍然是一个挑战。令人惊讶的是，没有临床批准的技术可以 直接加强头颈部肿瘤切除和组织保存的术中指导， 这通常通过解剖学知识、视觉提示和触诊来执行。荧光引导 外科（FGS）已经成功地融入临床医学，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区域中操作，其中组织染色体- 光吸收、自发荧光和散射降至局部最小值，从而实现高对比度和高分辨率 成像深度可达一厘米肿瘤特异性FGS的术中指导可以显著改善 头颈部肿瘤患者的手术结果，为手术提供了一个新的范例。一个重要的骗局- 广泛临床采用的考虑因素是易于在当前手术工作流程中实施。如今 大多数正在开发的FGS造影剂被归类为“始终开启”探针，其中连续 荧光发射在整个成像过程中发生，而与探针与其结合靶的接近度无关。关- 这些始终开启的探针的靶向积累导致背景信号升高， 清除非特异性探针积累以产生足够的肿瘤-回- 地面比率（TBR）用于手术期间的决策。患者需要接受造影剂注射， 手术前几天。对于患者来说，这意味着额外的医院访问，带来额外的费用和压力。这 部分原因是探针尺寸大，导致外渗有限、循环时间长和肿瘤受损 渗透。为了缓解这些挑战，具有高特异性和亲和力的较小的靶向部分被高度修饰。 期望在全身给药后不久提供上级TBR，允许容易地整合到前 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 未满足的临床需求。我们将开发一流的近红外荧光探针，靶向突变的EGFR在头部 和颈部癌症，其中高TBR对于准确的肿瘤边缘评估至关重要，检测小的 肿瘤结节、残留病变和多灶性病变。这些新型荧光探针作为术中辅助工具 能够以高灵敏度和特异性在真实的时间内识别和区分这些肿瘤， 显著降低头颈部肿瘤患者的切缘阳性率，改善手术效果。