A novel diagnostic test for Irinotecan and Topotecan sensitivity

描述(由申请人提供)：这项第一阶段研究的长期目标是产生一种基于抗体的诊断分析，以检测肿瘤对从喜树碱衍生的一种广泛使用的化疗药物的反应，该药物来自喜树碱，包括伊立替康和拓扑替康。该检测将基于一种与细胞对喜树碱的敏感性相关的新生物标记物，并将用于临床应用，以区分可能对喜树碱衍生疗法有反应的癌症患者和那些不太可能对其有反应的癌症患者。有了这些信息，医生可以定制治疗方案，以更好地适应单个患者的肿瘤表型，从而提高成功治疗的机会。由于喜树碱衍生的化疗药物在多种癌症治疗中的广泛应用，对这类药物的诊断分析存在着迫切而未得到满足的需求。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，即一些患者将暴露在治疗的毒副作用中，而没有治疗益处，并将失去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记物作为喜树碱敏感性指示物的有效性，使用现有的兔多克隆抗体来筛选一组癌症来源的和正常的细胞系，(2)评估另外两种可能的检测形式，以及(3)生产和评价针对该生物标记物的单抗。这项研究将使用标准的生物技术，包括基于细胞的活性分析、免疫印迹分析、酶联免疫吸附试验、免疫组织化学和酶分析。这项研究的结果将用于支持对人类肿瘤标本进行更大的第二阶段评估，并推动进一步的商业开发。 公共卫生相关性：该项目将开发一种临床检测方法，以确定肿瘤可能对基于喜树碱的化疗药物有反应的癌症患者，并将他们与不太可能有反应的患者区分开来。由于很大一部分肿瘤由于尚不清楚的原因而对治疗没有反应，而且目前几乎没有可用的工具来预测肿瘤的反应，因此一些患者接受错误治疗的风险很大。因此，这项研究解决了对更好的诊断工具的迫切和未得到满足的需求，以供医生用来设计更个性化的治疗方案。

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.