A novel diagnostic test for Irinotecan and Topotecan sensitivity

伊立替康和拓扑替康敏感性的新型诊断测试

基本信息

批准号：
8198398
负责人：
RUTH A GJERSET
金额：
$ 20.58万
依托单位：
RG BIOPHARMA, LLC
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8198398
关键词：
Address Adverse effects Antibodies Biological Biological Assay Biological Markers Camptothecin Cancer Patient Cancer cell line Cell Line Cells Clinical Detection Development Diagnostic Diagnostic tests Ensure Enzyme-Linked Immunosorbent Assay Epitopes Evaluation Human Immunoblot Analysis Immunoblotting Immunofluorescence Immunologic Immunohistochemistry Individual Knowledge Link Malignant Neoplasms Mediating Monoclonal Antibodies Normal Cell Oryctolagus cuniculus Patients Pharmaceutical Preparations Phase Phenotype Phospho-Specific Antibodies Phosphorylation Site Phosphoserine Physicians Protein-Serine-Threonine Kinases Proteins Resistance Risk Serine Site Specimen Techniques Testing Therapeutic Time Topotecan Treatment Protocols Treatment outcome Type I DNA Topoisomerases Western Blotting base cancer cell cell fixing chemotherapeutic agent clinical application design human TOP1 protein improved irinotecan monoclonal antibody production novel novel diagnostics phase 1 study polyclonal antibody resistance mechanism response tool tumor

项目摘要

DESCRIPTION (provided by applicant): The long term objective of this Phase 1 study is to produce an antibody-based diagnostic assay to detect tumor responsiveness to a widely used class of chemotherapeutic agents derived from camptothecin that includes Irinotecan and Topotecan. The assay will be based on a novel biomarker associated with cellular sensitivity to camptothecin and will have clinical application to distinguish cancer patients likely to respond to camptothecin-derived therapeutics from those unlikely to respond. With this information, the physician can tailor the treatment regimen to be better adapted to the individual patient's tumor phenotype, thereby improving the chances of successful treatment. There is an urgent and unmet need for diagnostic assays of this type for camptothecin-derived chemotherapeutic drugs because of the wide application of these drugs today in the treatment of a variety of cancers. Nevertheless, because a substantial fraction of tumors do not respond to therapy due to poorly understood resistance mechanisms, and because there are presently few diagnostic tools available to the physician to predict therapy responses, there is a significant risk that some patients will be exposed to the toxic side effects of treatment without therapeutic benefit, and will lose time that could have been used for other treatments. The Specific Aims of the project are to are (1) to use immunoblot analysis to validate the biomarker as an indicator of camptothecin sensitivity using an available rabbit polyclonal antibody to screen a panel of cancer-derived and normal cell lines, (2) to evaluate 2 additional possible assay formats, and (3) to produce and evaluate a monoclonal antibody to this biomarker. The study will employ standard biological techniques, including cell-based viability assays, Western immunoblot assays, ELISA assays, immunohistochemistry, and enzymatic assays. The results of this study will be used to support a larger Phase 2 evaluation of human tumor specimens and to advance further commercial development. PUBLIC HEALTH RELEVANCE: This project will develop a clinical assay to identify cancer patients whose tumors are likely to respond to camptothecin-based chemotherapeutic drugs, and distinguish them from patients unlikely to respond. Because a substantial fraction of tumors do not respond to therapy for reasons that remain unclear, and because there are presently few tools available for predicting tumor responsiveness, there is a significant risk that some patients will receive the wrong treatment. The study therefore addresses the urgent and unmet need for better diagnostic tools to be used by physicians to design more individualized treatment regimens.

描述（由申请人提供）：该 1 期研究的长期目标是产生一种基于抗体的诊断测定法，以检测肿瘤对广泛使用的一类源自喜树碱的化疗药物（包括伊立替康和拓扑替康）的反应性。该测定将基于一种与细胞对喜树碱敏感性相关的新型生物标志物，并将具有临床应用来区分可能对喜树碱衍生疗法产生反应的癌症患者与那些不太可能产生反应的癌症患者。有了这些信息，医生就可以调整治疗方案，以更好地适应个体患者的肿瘤表型，从而提高治疗成功的机会。由于喜树碱衍生的化疗药物如今广泛应用于治疗多种癌症，因此对这种类型的喜树碱化疗药物的诊断测定存在迫切且未满足的需求。然而，由于对耐药机制知之甚少，相当一部分肿瘤对治疗没有反应，而且目前医生可用于预测治疗反应的诊断工具很少，因此存在一些患者暴露于治疗反应的重大风险。治疗的毒副作用没有治疗益处，并且会浪费本可用于其他治疗的时间。该项目的具体目标是 (1) 使用免疫印迹分析来验证生物标志物作为喜树碱敏感性的指标，使用可用的兔多克隆抗体来筛选一组癌症来源和正常细胞系，(2) 评估2 种其他可能的测定形式，以及 (3) 产生和评估针对该生物标志物的单克隆抗体。该研究将采用标准生物技术，包括基于细胞的活力测定、蛋白质免疫印迹测定、ELISA 测定、免疫组织化学和酶测定。这项研究的结果将用于支持对人类肿瘤标本进行更大规模的二期评估，并推动进一步的商业开发。公共健康相关性：该项目将开发一种临床检测方法，以识别其肿瘤可能对基于喜树碱的化疗药物产生反应的癌症患者，并将他们与不太可能产生反应的患者区分开来。由于大部分肿瘤对治疗没有反应的原因尚不清楚，而且目前可用于预测肿瘤反应性的工具很少，因此存在一些患者接受错误治疗的巨大风险。因此，该研究解决了医生使用更好的诊断工具来设计更个性化的治疗方案的迫切且未得到满足的需求。