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.

开发用于早期检测头颈癌的灵敏且特异的诊断方法 仍然是未满足的医疗需求。大多数正在开发的检测方法依赖于肿瘤细胞生物标志物，通常存在于 仅一部分肿瘤细胞和/或头颈鳞状细胞癌患者的子集 （HNSCC）。因此，单个患者内和患者之间肿瘤细胞的内在异质性 事实上限制了这些测定的灵敏度。为了解决这个问题，我们建议监测 HNSCC 使用识别肿瘤浸润骨髓细胞的 RNA 适体来检测口腔冲洗液中的存在。这些细胞 在肿瘤发生早期大量浸润病灶，参与肿瘤发生和发展 进展，并预测 HNSCC 的复发。此外，这些细胞在肿瘤中快速更新 微环境并将其内容物释放到肿瘤微环境和附近的液体中。 我们鉴定了四种 RNA 适体，它们能够识别骨髓源性抑制细胞和巨噬细胞。 在所有接受评估的患者中，HNSCC 肿瘤而非血液或健康组织中的骨髓对应物。 此外，我们的可行性和原理实验证明表明这些适体可能会歧视 头颈癌患者的口腔冲洗液来自健康捐赠者的口腔冲洗液。我们建议测试 假设线性表面等离子共振 (LSPR) 实验中使用的 MDSC 特异性适体可以 从口腔冲洗液中检测 HNSCC，具有高灵敏度和特异性。我们将首先使用以下方法优化测定 样品已存入我们的机构。然后，我们将进行一项前瞻性临床研究，我们将测试 来自 150 名经活检证实的 HNSCC 患者（所有阶段、所有部位）和 150 名年龄匹配的健康患者的口腔冲洗液 捐助者。特别是，我们将并排比较使用配体的 LSPR 测定的灵敏度和特异性 我们的 MDSC 特异性适体或抗 CD44 的抗体，CD44 是与 HNSCC 密切相关的标记物 正在开发用于通过口腔冲洗诊断 HNSCC 的方法，并取得了有希望的结果。 总之，我们提出了一种早期诊断 HNSCC 的新方法，这种疾病通常只被诊断出来 处于晚期时，预后较差，治疗发病率较高。我们的假设应该是 确实，我们预计基于 MDSC 的检测可能有助于及早检测这种恶性肿瘤 治疗最有效且侵入性较小的阶段。