Development of aptamer-based detection and therapy strategies for ovarian cancer

开发基于适体的卵巢癌检测和治疗策略

• 批准号: 8180421
• 负责人: Rebecca Jean Whelan
• 金额: $ 34.51万
• 依托单位: OBERLIN COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8180421
• 关键词: Adverse effects; Affinity; Antibodies; Aptamer Technology; Back; Binding; Biological; Biological Assay; Biological Markers; Blood; CA-125 Antigen; Capillary Electrophoresis; Cell surface; Cells; Cessation of life; Complement; Detection; Development; Diagnosis; Diagnostic; Disease; Early Diagnosis; Enzyme-Linked Immunosorbent Assay; Epididymis; Fever; Fluorescence Polarization; General Population; Goals; Gold; Health Benefit; Home environment; Human; Image; Immobilization; In Vitro; Institution; Label; Ligands; Localized Malignant Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Mentors; Metals; Methods; Nucleic Acids; Outcome; Ovary; Patients; Pharmaceutical Preparations; Phototherapy; Physicians; Process; Proteins; Public Health; Research; Research Project Grants; Resolution; Sampling; Scanning Electron Microscopy; Screening for Ovarian Cancer; Screening for cancer; Screening procedure; Sensitivity and Specificity; Serum; Single-Stranded DNA; Spatial Distribution; Specificity; Spectrum Analysis; Staging; Students; Surface; Surface Plasmon Resonance; Survival Rate; Techniques; Temperature; Testing; Therapeutic; Time; Training; Translating; Tumor Markers; United States; Universities; Wisconsin; Woman; advanced disease; analytical method; aptamer; assay development; base; cancer cell; cancer diagnosis; cancer therapy; cell killing; cellular imaging; chemotherapy; college; improved; infancy; innovation; insight; interest; killings; medical schools; mesothelin; mortality; nanomaterials; nanoparticle; neoplastic cell; novel; ovarian neoplasm; research study; resilience; statistics; tumor

DESCRIPTION (provided by applicant): The need persists for better early detection of ovarian cancer. Currently, detection of ovarian cancer relies in part on the recognition of the tumor marker protein CA125 by antibody molecules. CA125 is the most widely assayed and best validated biomarker of ovarian cancer, but because available assays lack sufficient sensitivity and specificity, CA125 is not currently recommended for screening in the general population. More informative assays will result from the simultaneous detection of multiple cancer biomarkers, including those whose biological abundance complements CA125. Mesothelin and human epididymis protein 4 (HE4) are two relatively new biomarkers that may complement CA125 in serum tests. Currently, most assays for ovarian cancer markers rely on antibody molecules for selective recognition. Antibodies are limited in terms of their stability, reusability, and ability to be modified with imaging labels or immobilization tags. Assays incorporating aptamers (functional nucleic acid ligands) are an attractive alternative to antibody-based techniques. Aptamers are robust, easily labeled, and prepared entirely in vitro. In previous studies, some aptamers have been shown surpass antibodies in affinity for their target, which may translate into improved detection methods for cancer markers in serum tests. An additional application in which aptamers may replace antibodies is in targeting metal nanoparticle imaging agents or therapeutic payloads directly to surfaces of ovarian cancer cells. Such cell targeting may be useful for imaging the distribution of biomarkers on ovarian tumors and may enable localized cell killing by hyperthermia, reducing the need for systemic chemotherapy. The research plan proposed here aims to develop aptamers for three important ovarian cancer biomarkers. Assays that use these aptamers in conjunction with sensitive instrumental methods will then be developed. We will also perform proof-of-principle experiments in which aptamer-functionalized nanoparticles mediate high-resolution imaging and targeted hyperthermia. Public health will be positively impacted by the development of new CA125 assays to improve cancer screening and by innovative approaches to tumor cell eradication. The PI will conduct the metal nanoparticle assays during a one-year research sabbatical hosted at the University of Wisconsin Medical School (Year 1). Two additional years of support are requested during which the PI, back at her home institution of Oberlin College, will train two undergraduate students per year and mentor them in aptamer selection and assay development. A recently graduated Oberlin undergraduate will be employed as a full-time research technician in Year 3. PUBLIC HEALTH RELEVANCE: This research project is motivated by the need to develop reliable non-invasive tests for early stage ovarian cancer, since treatment is most effective when the disease is diagnosed early. Tests for biomarkers found in the blood of women with ovarian cancer are widely used by physicians; our goal is to develop new ways of measuring the amounts of three important cancer biomarkers. We also seek to develop new methods for looking at the surfaces of tumors and selectively killing cancer cells.

描述（由申请人提供）：需要更好地早期检测卵巢癌的需求。目前，检测卵巢癌部分依赖于抗体分子对肿瘤标记蛋白Ca125的识别。 CA125是卵巢癌的最广泛测定和最佳验证的生物标志物，但是由于可用的测定方法缺乏足够的敏感性和特异性，因此目前不建议在一般人群中筛查CA125。更有益的测定方法将是由于对多种癌症生物标志物的同时检测而产生的，包括生物丰度补充Ca125的生物标志物。间皮素和人类附子蛋白4（HE4）是两个相对较新的生物标志物，可以在血清测试中补充Ca125。当前，大多数卵巢癌标志物的测定法都依赖于抗体分子来选择性识别。抗体在其稳定性，可重复性和通过成像标签或固定标签进行修饰的能力方面受到限制。结合适体（功能性核酸配体）的测定是基于抗体技术的有吸引力的替代方法。适体功能强大，易于标记并完全在体外制备。在先前的研究中，已经显示了一些适体对其靶标的亲和力超过抗体，这可以转化为血清测试中癌症标志物的改进方法。适体可以替代抗体的另一种应用是将金属纳米颗粒成像剂或治疗有效载荷直接靶向卵巢癌细胞的表面。这种细胞靶向可能有助于对卵巢肿瘤上生物标志物的分布进行成像，并可能通过热疗杀死局部细胞，从而减少了全身化疗的需求。这里提出的研究计划旨在为三种重要的卵巢癌生物标志物开发适体。然后将开发与敏感仪器方法结合使用这些适体的测定法。我们还将执行原则证明实验，其中适体官能化纳米颗粒介导高分辨率成像和靶向高温。公共卫生将受到新的CA125测定法的开发，以改善癌症筛查以及通过消除肿瘤细胞的创新方法的积极影响。 PI将在威斯康星大学医学院（1年级）的一年休假期间进行金属纳米颗粒测定法。要求另外两年的支持，在此期间，PI回到她的家乡奥伯林学院，每年将培训两名本科生，并指导他们进行适体选择和分析开发。最近毕业的Oberlin本科生将被任命为第三年级的全日制研究技术员。 公共卫生相关性：该研究项目是出于为早期卵巢癌开发可靠的非侵入性测试的必要性，因为当疾病及早诊断时，治疗是最有效的。医生广泛使用了卵巢癌女性血液中发现的生物标志物的测试；我们的目标是开发新的方法来衡量三种重要的癌症生物标志物的数量。我们还寻求开发新方法，以查看肿瘤的表面并有选择地杀死癌细胞。