TAS::75 0849::TAS PHARMACODYNAMIC ASSAYS FOR CANCER THERAPEUTICS

将使用Meso Scale Diagnostics（MSD）多阵列技术开发测量与癌症相关的细胞蛋白水平的药效学测定。这些测定将适用于真实的时间临床前和临床样品测试，并且应允许快速评价治疗、反应、测量治疗与肿瘤停滞/消退的对应性，允许临床试验的患者分层，并促进在药物开发的早期阶段的癌症治疗的临床验证。试验将在临床前模型中进行证明，即人实体瘤的小鼠异种移植物和代表不同癌症亚型的分子特征癌细胞系。在可能的情况下，将优化的检测方法应用于选定药物治疗前后的患者肿瘤活检或替代组织（视情况而定）。所使用的治疗剂将主要靶向PI 3 k/Akt/mTOR和MAPK信号传导通路，并且所选择的标记物与这些通路相关。MSD的多重能力（包括测量几个目标的总和磷酸化形式，精密的检测灵敏度，最小的样品要求和广泛的动态范围，使这项技术非常适合实现NCI的分子药效学应用的目标。

Pharmacodynamic assays that measure levels of cellular proteins of relevance to cancer will be developed using Meso Scale Diagnostics (MSD) MULTI-ARRAY technology. These assays will be suitable for ¿real time¿ preclinical and clinical sample testing, and should allow rapid evaluation of treatment, responses, gauge treatment correspondence to tumor stasis/regression, allow patient stratification for clinical trials and facilitate clinical validation of cancer therapeutics at early stages of drug development. Assays will be demonstrated in pre-clinical models, namely mouse xenographs of human solid tumors and molecularly characterized cancer cell lines representing different cancer subtypes. Optimized assays will be applied to patient tumor biopsies or surrogate tissues as appropriate, from patients before and after selected drug treatments where possible. The therapeutic agents used will primarily target the PI3k/Akt/mTOR and MAPK signaling pathways, and markers selected are relevant to these pathways. MSD¿s multiplex capability (including measuring total and phosphorylated forms of several targets, exquisite assay sensitivity, minimal sample requirement and wide dynamic ranges make this technology ideally suited to achieving the NCI¿s objectives for molecular pharmacodynamic applications.