Proteogenomic Translational Research Center for Clinical Proteomic

项目总结 太平洋西北蛋白质基因组翻译研究中心(PNPTRC)有两个主要目标： 1)使用蛋白质丰度和翻译后修饰的联合测量，特别是 磷酸化，以建立可有效用于指导药物选择的药物反应的预测模型 用于一线治疗的代理，以及2)对信号串扰和冗余的过程进行建模 有效预测耐药性，指导二线治疗。为了实现这些目标， PNPTRC将利用正在进行的个体化治疗选择策略的临床前和临床研究 针对急性髓系白血病(AML)，改进基于DNA和RNA数据的新兴模型，以 包括来自蛋白质组和磷蛋白质组信号转导途径信息 测量，并通过整合基因组和蛋白质组数据来提高模型的预测能力。 PNPTRC代表了创新的临床试验设计和治疗干预之间的合作 在俄亥俄州立大学奈特癌症中心，以及位于 PNNL。PNPTRC的临床前研究部门将确定蛋白质丰度和蛋白质的差异 在俄亥俄州立大学开发的体外IC50试验中，与细胞存活密切相关的磷酸化。 随着治疗时间的推移，蛋白质丰度和磷酸化的测量将被用来建立网络 途径激活和串扰可以通知最终抗药性的可能性并确定替代方案 可作为二线治疗靶点的信号通路。这些型号将进行进一步的测试和 在随后的体外实验中使用暴露于特定组合的原代人AML细胞进行精炼 抑制剂。临床研究部门将对AML样本进行高质量的靶向蛋白质组分析 患者参加NCI赞助的临床试验，以确认特定差异的预测能力 临床前研究中发现的蛋白质丰度和/或磷酸化。

PROJECT SUMMARY The Pacific Northwest Proteogenomic Translational Research Center (PNPTRC) has two overarching aims: 1) to use combined measurements of protein abundance and post translational modifications, particularly phosphorylation, to build predictive models of drug response that can be effectively used to guide the choice of agents for first-line therapies, and 2) to model the processes of signaling crosstalk and redundancy to more effectively predict drug resistance and to guide second line therapies. To accomplish these goals, the PNPTRC will leverage on-going preclinical and clinical studies of individualized treatment selection strategies for acute myelogenous leukemia (AML) to improve the emerging models based on DNA and RNA data to include signal transduction pathway information derived from proteomic and phosphoproteomic measurements, and improve the predictive power of the models by integrating genomic and proteomic data. The PNPTRC represents a collaboration between innovative clinical trial design and therapeutic interventions at the OHSU Knight Cancer Center, and cutting edge mass spectrometry-based proteomics technologies at PNNL. The Preclinical Research Arm of the PNPTRC will identify differences in protein abundance and protein phosphorylation that correlate strongly with cell survival in the in vitro IC50 assay developed at OHSU. Measurements of protein abundance and phosphorylation over time of treatment will be used to build networks of pathway activation and crosstalk that can inform the likelihood of eventual resistance and identify alternative signaling pathways which can be targeted in second line therapies. The models will be further tested and refined in subsequent ex vivo experiments using primary human AML cells exposed to specific combinations of inhibitors. The Clinical Research Arm will apply high quality targeted proteomic assays on samples from AML patients enrolled in NCI-sponsored clinical trials to confirm the predictive abilities of specific differences in protein abundance and/or phosphorylation identified in the Preclinical Research Arm.