A novel diagnostic test for Irinotecan and Topotecan sensitivity

描述（由申请方提供）：这项I期研究的长期目标是生产一种基于抗体的诊断试验，以检测肿瘤对广泛使用的一类喜树碱衍生化疗药物（包括伊立替康和拓扑替康）的反应性。该测定将基于与细胞对喜树碱的敏感性相关的新型生物标志物，并将具有临床应用，以区分可能对喜树碱衍生的治疗剂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，从而提高成功治疗的机会。对喜树碱衍生的化疗药物的这种类型的诊断测定存在迫切且未满足的需求，因为这些药物如今广泛应用于治疗各种癌症。然而，由于对耐药机制知之甚少，相当一部分肿瘤对治疗无反应，并且由于目前医生可用于预测治疗反应的诊断工具很少，因此存在一些患者将暴露于治疗的毒副作用而无治疗益处的显著风险，并且将损失本可用于其他治疗的时间。该项目的具体目的是（1）使用免疫印迹分析验证生物标志物作为喜树碱敏感性的指示剂，使用可用的兔多克隆抗体筛选一组癌症衍生和正常细胞系，（2）评价2种其他可能的测定形式，以及（3）生产和评价该生物标志物的单克隆抗体。该研究将采用标准生物学技术，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。本研究的结果将用于支持对人类肿瘤标本进行更大规模的II期评价，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，以识别肿瘤可能对基于喜树碱的化疗药物产生反应的癌症患者，并将其与不太可能产生反应的患者区分开来。由于相当一部分肿瘤对治疗没有反应，原因尚不清楚，而且目前几乎没有工具可用于预测肿瘤反应性，因此存在一些患者接受错误治疗的重大风险。因此，这项研究解决了医生设计更个性化治疗方案时对更好的诊断工具的迫切和未满足的需求。

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.