TAS::75 0849::TAS PHARMACODYNAMIC ASSAYS FOR WNT/FRIZZLED AND HGF/C-MET SIGNALIN

NCI的高优先级药效学目标的多路分析将利用中间尺度诊断(MSD)多阵列技术开发，以促进从单个肿瘤活检或替代组织样本中进行多个综合药效学读数。这些分析方法将适用于结合治疗药物的临床前开发来测量分子水平的治疗反应。将开发检测方法来评估Wnt/Frizzed和HGF/c-Met信号通路在包括肾细胞癌(RCC)在内的许多恶性肿瘤中的作用。这些分析方法将在临床前模型、特征化的细胞系、肿瘤异种移植组织和患者血浆样本中得到验证。在随后的第二阶段工作中，将与NCI合作，将优化的分析应用于患者样本。临床前样本将来自商业供应商，或由我们的合作者Mier博士和Panka博士(哈佛大学)提供，这些样本来自正在进行的癌症治疗效果研究。MSD的多重能力(包括测量总的和磷酸化的信号蛋白)、精致的分析灵敏度、最少的样品需求、宽的动态范围和易于分析的可扩展性，使这项技术非常适合于实现NCI的分子药效学应用目标。这项研究将为临床试验中评估和验证新的抗癌药物提供有价值的工具，并最终用于临床监测治疗。

Multiplexed assays for pharmacodynamic targets of high priority for the NCI will be developed using Meso Scale Diagnostics' (MSD) Multi-Array technology to facilitate multiple integrated pharmacodynamic readouts from a single tumor biopsy or surrogate tissue specimen. These assays will be suitable for measurement of molecular-level responses to treatment in conjunction with preclinical development of therapeutic agents. Assays will be developed to evaluate the Wnt/Frizzled and HGF/c-Met signaling pathways implicated in many malignancies, including renal cell carcinoma (RCC). These assays will be demonstrated in pre-clinical models, characterized cell lines, tumor xenograft tissues, and patient plasma samples. Optimized assays will be applied to patient samples in subsequent Phase 2 work, in collaboration with the NCI. Pre-clinical samples will be from commercial vendors or provided by our collaborators, Drs. Mier and Panka (Harvard University) from ongoing studies on treatment effects in cancer. MSD's multiplex capability (including measuring total and phosphorylated signaling proteins), exquisite assay sensitivity, minimal sample requirement, wide dynamic ranges, and ease of assay scalability, make this technology ideally suited to achieving the NCI's objectives for molecular pharmacodynamic applications. This research will provide valuable tools to evaluate and validate new anti-cancer agents in clinical trials and for eventual clinical use to monitor treatment.