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

• 批准号: 8729543
• 负责人: RUTH A GJERSET
• 金额: $ 24.03万
• 依托单位: RG BIOPHARMA, LLC
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-26 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8729543
• 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

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.

描述（由申请人提供）：该i期研究的长期目标是开发一种基于抗体的诊断方法，以检测肿瘤对喜树碱衍生的一类广泛使用的化疗药物的反应性，包括伊立替康和拓扑替康。该检测将基于一种与喜树碱细胞敏感性相关的新型生物标志物，并将在临床应用中区分可能对喜树碱衍生疗法有反应的癌症患者和不太可能有反应的癌症患者。有了这些信息，医生可以定制治疗方案，以更好地适应个体患者的肿瘤表型，从而提高成功治疗的机会。由于喜树碱衍生的化疗药物目前广泛应用于各种癌症的治疗，因此迫切需要这种类型的诊断分析。然而，由于对耐药机制知之甚少，很大一部分肿瘤对治疗没有反应，而且由于目前医生几乎没有可用的诊断工具来预测治疗反应，因此存在很大的风险，即一些患者将暴露于治疗的毒副作用而没有治疗效果，并且将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衍生和正常细胞系，(2)评估另外两种可能的检测格式，(3)生产和评估该生物标志物的单克隆抗体。该研究将采用标准的生物技术，包括基于细胞的活力测定、免疫印迹测定、ELISA测定、免疫组织化学和酶促测定。这项研究的结果将用于支持更大规模的人类肿瘤标本二期评估，并推进进一步的商业开发。