Development of an HPV-E6 Cervical Neoplasia Test for Use in Centralized Diagnosti

开发用于集中诊断的 HPV-E6 宫颈肿瘤检测

• 批准号: 8392904
• 负责人: Michael Paul Belmares
• 金额: $ 19.82万
• 依托单位: ARBOR VITA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-21 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8392904
• 关键词: Affect; Applications Grants; Attention; Automation; Biological Assay; Biological Markers; Biopsy; Cancer Etiology; Cancerous; Carcinogens; Cause of Death; Cells; Cellular Morphology; Centers for Disease Control and Prevention (U.S.); Cervical; Cessation of life; Clinic; Clinical; Clinical Research; Clinical Sensitivity; Colposcopy; Country; Detection; Developed Countries; Development; Diagnostic; Diagnostic tests; Direct Costs; Early Diagnosis; Epithelial Cells; Expenditure; Feasibility Studies; Future; Genes; Grant; HPV-High Risk; High Prevalence; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Immunoassay; Individual; Intervention; Lead; Lesion; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Medical; Methods; Molecular; Molecular Diagnostic Testing; Monoclonal Antibodies; Neoplasms; Nucleic Acids; Oncogene Proteins; Outcome; Pap smear; Papillomavirus; Pathologist; Patients; Phase; Population; Predictive Value; Proteins; Recombinants; Research Design; Risk; Sampling; Screening procedure; Sensitivity and Specificity; Severities; Severity of illness; Specificity; Specimen; Swab; Technology; Testing; Transcript; Translating; Validation; Viral; Visit; Visual; Woman; Women' s Health; arborvitae; base; cost; design; detector; effective therapy; follow-up; high throughput screening; meetings; mortality; prevent; product development; programs; prototype; response; tumorigenesis

DESCRIPTION (provided by applicant): Cervical cancer is the leading cause of cancer-related death in women. It causes over 250,000 death world-wide / year, with 80% occurring in countries without systematic cervical neoplasia screening programs5. High risk Human Papillomavirus (HPV) infection is responsible for >99% of all the cervical cancers4. Early detection of HPV infection by the Pap Test has reduced the death toll in developed nations significantly10. Despite its merits, the Pap Test is no longer considered an adequate screening technology due to the high false-negative and false-positive rates as a result of subjective visual interpretation of cell morphology by pathologists7. In recent years, several nucleic acid-based HPV diagnostic tests have emerged8. These tests have excellent clinical sensitivity, but fail to provide the desired clinical specificity, due to the high prevalence of HPV infection without pathological outcome8. Consequently, utilization of molecular HPV tests for screening may lead to costly over-treatment of patients (follow-up visits; colposcopies; biopsies). In response to the need for a specific yet sensitive screening method, Arbor Vita Corporation proposes the development of a diagnostic test that detects the Papillomavirus protein E6, a pivotal oncoprotein in cervical oncogenesis. E6 oncoprotein levels in cervical swab specimens from patients with neoplasia correlate positively with the severity of lesions6. Accordingly, an HPV-E6 oncoprotein-based screening test has the potential to identify HPV-positive women who are at risk to develop cervical cancer amidst the much larger number of women with clinically irrelevant HPV infection. In this grant, the applicants propose the development of a high-throughput bead-based assay to detect and to type E6 oncoproteins from 15 high-risk HPV types for use in centralized clinical labs. The new HPV-E6 oncoprotein test will harness the technological advances in bead-based immunoassays and the availability of highly specific HPV-E6 monoclonal antibodies at Arbor Vita to achieve the desired high sensitivity, specificity and capability for automation. Under phase 1, our approach is focused on the development of the bead-based 15 HPV type E6 oncoprotein diagnostic prototype test. Upon successful completion of phase 1, the applicants will submit a phase 2 grant application for further product development towards the final format of the test that will be used in clinical studies for design validation. PUBLIC HEALTH RELEVANCE: Cervical cancer is caused by HPV and is worldwide a leading cause of death in women; implementation of sensitive and specific screening technology is the key to reduced mortality. The Pap Test screening method is no longer considered adequate. The applicants propose the development of an HPV-E6 oncoprotein based test for cervical neoplasia screening. Via detection of E6, the cancer causing agent, the technology promises to identify those women who need clinical attention, among many more women who have HPV infection without clinical outcome. This should translate to public heath cost-saving by reducing the number of unnecessary clinical follow-up and treatment.

描述(申请人提供)：宫颈癌是女性癌症相关死亡的主要原因。它每年导致全世界超过250,000人死亡，其中80%发生在没有系统的宫颈肿瘤筛查计划的国家5。高危人乳头瘤病毒(HPV)感染导致了99%的宫颈癌4。通过巴氏试验及早发现HPV感染，大大减少了发达国家的死亡人数。尽管巴氏试验有其优点，但由于主观视觉导致的高假阴性和假阳性率，它不再被认为是一种适当的筛查技术 病理学家对细胞形态的解释7。近年来，出现了几种基于核酸的HPV诊断测试8。这些检测具有极好的临床敏感性，但由于HPV感染的高流行率而没有病理结果，因此无法提供所需的临床特异性。因此，利用分子HPV检测进行筛查可能会导致患者过度治疗(随访、镜检查、活组织检查)。为回应这一事件 由于需要一种特殊而敏感的筛查方法，Arbor Vita Corporation建议开发一种诊断测试，以检测乳头瘤病毒蛋白E6，这是宫颈肿瘤发生中的一种关键癌蛋白。肿瘤患者宫颈拭子标本中的E6癌蛋白水平与病变的严重程度呈正相关。因此，基于HPV-E6癌蛋白的筛查试验有可能在大量临床无关的HPV感染妇女中识别出HPV阳性妇女患宫颈癌的风险。在这项赠款中，申请者建议开发一种高通量的基于珠子的检测方法，以检测和分型15种高危HPV类型的E6癌蛋白，用于集中式临床实验室。新的HPV-E6癌蛋白检测将利用基于珠子的免疫分析技术的进步，以及Arbor Vita公司高度特异的HPV-E6单抗的可用性，以实现所需的高灵敏度、特异度和自动化能力。在第一阶段，我们的方法集中在基于珠子的15HPV型E6癌蛋白诊断原型测试的开发上。在第一阶段成功完成后，申请者将提交第二阶段拨款申请，以进一步开发产品，以实现测试的最终格式，该测试将用于临床研究以进行设计验证。 公共卫生相关性：宫颈癌是由人乳头瘤病毒引起的，是全世界妇女死亡的主要原因；实施敏感和特异的筛查技术是降低死亡率的关键。巴氏试验筛查方法不再被认为是合适的。申请人建议开发一种基于HPV-E6癌蛋白的检测方法，用于宫颈肿瘤的筛查。通过检测致癌物质E6，这项技术有望在更多感染HPV但没有临床结果的女性中识别出那些需要临床关注的女性。这应该转化为通过减少不必要的临床随访和治疗的数量来节省公共卫生成本。