TAS::75 0849::TAS SBIR TOPIC 292 PHASE I DEVELOPMENT OF MOLECULAR PHARMACODYNAMI

罗恩和c-MET信号通路是细胞生长、存活、迁移、分化和耐药性的关键调节因子。在许多人类癌症中观察到高水平的活化罗恩或c-MET。通过磷酸化激活罗恩和c-MET启动促进癌细胞增殖、侵袭、凋亡和耐药性以及转移的信号转导级联。目前在临床试验中的许多抗癌药物都针对这两种途径。此外，罗恩和c-MET的活化状态和蛋白水平是药物治疗功效和癌细胞存活结果的良好指标。在第一阶段，我们将开发一种定量免疫测定法，以监测各种活化和未活化癌细胞系中罗恩或GAB 1（c-MET的靶点）的磷酸化状态。将生产ELISA试剂盒并创建书面SOP。在第二阶段，我们将使用罗恩或GAB 1试剂盒来测量来自各种癌症和其他PD检测的临床样本中的激活和蛋白水平，包括使用上调或下调这些靶点的药物的研究。罗恩和GAB 1检测试剂盒的可用性将帮助临床医生和研究人员监测许多疾病中的这些蛋白质，并预测癌症治疗的疗效。

The RON and c-MET signal pathways are critical regulators of cell growth, survival, migration, differentiation, and drug resistance. High levels of activated RON or c-MET have been observed in a number of human cancers. Activation of RON and c-MET by phosphorylation initiates a signal transduction cascade that promotes cancer cell proliferation, invasiveness, apoptotic and drug resistance, and metastasis. A number of anticancer drugs currently in clinical trials are targeting both of of these pathways. Further, the activation state and protein levels of RON and c-MET are good indicators of drug treatment efficacy and cancer cell survival outcome. In Phase I, we will develop a quantitative immunoassay to monitor the phosphorylation state of either RON or GAB1 (the target of c-MET) in various activated and unactivated cancer cell lines. The ELISA kit will be manufactured and written SOPs created. In Phase II, we will use the RON or GAB1 kit to measure activation and protein levels in clinical samples from a wide range of cancers and additional PD assays, including studies using drugs that upregulate or downregulate these targets. The availability of RON and GAB1 detection kits will aid clinicians and researchers to monitor these proteins in a number of diseases and predict the efficacy of cancer treatment.