NANOTECHNOLOGIES FOR QUANTITATING PI3-KINASE PATHWAY BIOMARKERS

靶向癌症治疗的临床评价目前受到难以匹配新的靶向药物的阻碍。 将分子靶向剂输送至适当的分子定义的患者。解决方案需要使用 基于分子的生物标志物，以指导患者选择，优化药物剂量和评估反应， 治疗该项目将使用两个注释良好的，遗传定义的人类前列腺小鼠模型 发现定义疾病进展、起始致癌病变和反应的生物标志物 接受治疗这些小鼠模型的分子特征与人类前列腺癌非常相似， 美国对它们用于发现人类肿瘤生物标志物的效用的信心。此外，我们已经 证明了疾病阶段和起始分子损伤的主要分子特征是 这两种模式都很容易识别。该项目的目标1将使用现有的mRNA和蛋白质组学数据集， 确定来自肿瘤组织的最佳mRNA特征和来自血清的蛋白质特征， 疾病阶段、分子病变和治疗反应（与Hood实验室合作）。然后我们将 开发纳米装置，用于测量来自少量细胞的这些mRNA特征（与 与Fluidigm合作）和基于Si的纳米器件用于测量血清蛋白特征（与 Heath实验室）。然后，我们将评估和优化这些纳米器件在小鼠（目标2）和 接受两种不同激酶抑制剂治疗以及使用更常规血液的患者（目标3） 这些研究的蛋白质组学分析（与胡德实验室合作）。该项目的成功将提供 在治疗前和治疗期间使用高分子药物对癌症患者进行详细的分子评估的概念验证 准确、经济、微创的技术。

Clinical evaluation of targeted cancer therapy is currently hampered by the difficulty in matching a new molecularly targeted agent to the appropriate molecular-defined patient. The solution requires the use of molecularly-based biomarkers to guide patient selection, optimize drug dosage and assess response to treatment. This project will use two well-annotated, genetically-defined mouse models of human prostate cancer to discover biomarkers that define disease progression, the initiating oncogenic lesion and response to therapy. The molecular profiles of these mouse models closely resemble human prostate cancers, giving us confidence in their utility for discovery of human tumor biomarkers. In addition, we have already demonstrated that dominant molecular signatures of disease stage and the initiating molecular lesion are easily detected in both models. Aim 1 of this project will use existing mRNA and proteomics datasets to define the optimal mRNA signatures from tumor tissue and protein signatures from serum to determine disease stage, molecular lesion and response to therapy (in collaboration with the Hood lab). We will then develop nanodevices for measuring these mRNA signatures from small numbers of cells (in collaboration with Fluidigm) and Si-based nanodevices for measuring serum protein signatures (in collaboration with the Heath lab). We will then evaluate and optimize the performance of these nanodevices in mice (Aim 2) and in patients (Aim 3) treated with two different kinase inhibitors as well as using more conventional blood proteomics analyses for these studies (in collaboration with Hood lab). Success in the project will provide proof-of-concept for detailed molecular evaluation of cancer patients before and during therapy using highly accurate, cost-effective and minimally invasive technologies.