Aptamer specific for myeloid derived suppressor cells for the diagnosis of head and neck cancer from the oral rinse

骨髓源性抑制细胞特异性适体，用于通过口腔冲洗液诊断头颈癌

• 批准号: 10665377
• 负责人: Elizabeth J Franzmann
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-15 至 2025-03-14
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665377
• 关键词: Age; Antibodies; Antigens; Benign; Biological Assay; Biological Markers; Biopsy; Blood; CD44 gene; Cancer Patient; Case/Control Studies; Cells; Circulation; Clinic; Clinical; Clinical Research; Communities; Data; Detection; Development; Diagnosis; Diagnostic tests; Dimensions; Disease; Early Diagnosis; Enrollment; Epitopes; Goals; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Head and neck structure; Heterogeneity; Histologic; Human; Human Papillomavirus; Immunologic Surveillance; Infiltration; Institution; Label; Larynx; Lesion; Ligands; Lipids; Liquid substance; Macrophage; Malignant - descriptor; Malignant Neoplasms; Medical; Monitor; Morbidity - disease rate; Mouth Neoplasms; Myelogenous; Myeloid Cells; Myeloid-derived suppressor cells; Neoplasms; Oligonucleotides; Operative Surgical Procedures; Oral; Oral Diagnosis; Oral cavity; Oropharyngeal; Otolaryngology; Patients; Peptides; Phenotype; Population; Prognosis; Proteins; Proteomics; RNA; Recording of previous events; Recurrence; Resistance; Resolution; Ribonucleases; Role; Running; Saliva; Sampling; Sensitivity and Specificity; Side; Site; Specificity; Structure; Surface Plasmon Resonance; Survival Rate; Techniques; Testing; Therapeutic; Time; Tissues; Toxin; Tumor Escape; Tumor Markers; Tumor Promotion; Tumor stage; Vertebral column; aptamer; chemical synthesis; cohort; combinatorial; cost; diagnostic assay; diagnostic tool; experimental study; head and neck cancer patient; human disease; hypopharynx; malignant mouth neoplasm; neoplastic; neoplastic cell; noninvasive diagnosis; novel strategies; pathogen; patient subsets; prospective; proteomic signature; synthetic antibodies; tumor; tumor growth; tumor initiation; tumor microenvironment; tumor progression; tumorigenesis

The development of sensitive and specific diagnostic assays for the early detection of Head and Neck Cancer is still an unmet medical need. Most assays being developed rely on a neoplastic cell biomarker often present in only a proportion of neoplastic cells and/or a subset of patients with Head and Neck Squamous Cell carcinoma (HNSCC). As such, the intrinsic heterogeneity of the neoplastic cell within a single patient and across patients de facto limits the sensitivity of these assays. To overcome this problem, we propose to monitor HNSCC presence in the oral rinse using RNA aptamers that recognize tumor-infiltrating myeloid cells. These cells infiltrate the lesion in high numbers and early during tumorigenesis, participate in tumor initiation and progression, and predict recurrence in HNSCC. Additionally, these cells are quickly renewed in the tumor microenvironment and release their content in the tumor microenvironment and nearby fluid. We identified four RNA aptamers that recognize myeloid derived suppressor cells and macrophages in the HNSCC tumor but not the myeloid counterparts in the blood or healthy tissues in all patients evaluated. Additionally, our feasibility and proof of principle experiments indicate that these aptamers might discriminate oral rinses of patients with head and neck cancers from those of healthy donors. We propose to test the hypothesis that MDSC-specific aptamers used in linear surface plasmon resonance (LSPR) experiments can detect HNSCC from the oral rinse with high sensitivity and specificity. We will first optimize the assay using samples already banked in our institution. Then, we will perform a prospective clinical study in which we will test oral rinses from 150 patients with biopsy-proven HNSCC (all stage, all sites) and 150 age-matched healthy donors. In particular, we will compare side-by-side the sensitivity and specificity of LSPR assays using as ligand either our MDSC specific aptamers or an antibody against CD44, a marker strongly associated with HNSCC that is being developed for HNSCC diagnosis from the oral rinse with promising results. In summary, we propose a novel approach for the early diagnosis of HNSCC, a disease often diagnosed only in advanced stages when the prognosis is poor, and the treatment morbidity is high. Should our hypothesis be true, we anticipate that assays based on the presence of MDSC may aid in detecting this malignancy at earlier stages when treatments are most effective and less invasive.

早期发现头颈癌的敏感和特定诊断测定的开发是 仍然是未满足的医疗需求。开发的大多数测定都取决于通常存在于 只有一部分肿瘤细胞和/或头颈部鳞状细胞癌患者的子集 （HNSCC）。因此，单个患者和跨患者的肿瘤细胞的固有异质性 事实上，限制了这些测定的敏感性。为了克服这个问题，我们建议监视HNSCC 使用RNA适体在口腔冲洗中的存在，这些RNA适体识别肿瘤浸润的髓样细胞。这些细胞 在肿瘤发生期间渗入高数量和早期的病变，参与肿瘤的启动和 进展，并预测HNSCC中的复发。此外，这些细胞在肿瘤中迅速更新 微环境并释放其含量在肿瘤微环境和附近的流体中。 我们确定了四个识别髓样衍生的抑制细胞和巨噬细胞的RNA适体 在所有评估的患者中，HNSCC肿瘤但不是血液或健康组织中的髓样肿瘤。 此外，我们的可行性和原理实验的证明表明这些适体可能会歧视 来自健康供体的头颈部癌症患者的口腔冲洗。我们建议测试 假设在线性表面等离子体共振（LSPR）实验中使用的MDSC特异性适体可以 从口腔冲洗中检测HNSCC，具有高灵敏度和特异性。我们将首先使用 样品已经在我们的机构中​​存储了。然后，我们将进行一项前瞻性临床研究，我们将在其中测试 来自150例活检证实HNSCC（所有阶段，所有站点）的口服冲洗和150个年龄匹配的健康 捐助者。特别是，我们将使用AS配体并排比较LSPR分析的灵敏度和特异性 我们的MDSC特异性适体或针对CD44的抗体，这是与HNSCC密切相关的标记 正在从口腔冲洗中开发用于HNSCC诊断，并有令人鼓舞的结果。 总而言之，我们提出了一种新的HNSCC早期诊断的方法，这种疾病通常仅被诊断 在预后较差时，在晚期阶段，治疗发病率很高。我们的假设应该是 没错，我们预计基于MDSC的存在的测定可能有助于检测早期的这种恶性肿瘤 治疗最有效且侵入性较小的阶段。