P3IK Signaling and Biology of Therapeutic Response in Brain and Prostate Tumors

描述（由申请人提供）：本申请加入了使用基因工程小鼠模型（GEMM）的两名医生-科学家领导者，以评估这些动物在临床前研究中的效用，这些研究可能直接影响人类临床试验。我们将研究实体瘤治疗反应的生物学，特别关注PI 3-激酶（PI 3 K）通路和对标准治疗有抗性的细胞。根据我们的专业知识，我们将比较和对比PI 3 K通路有助于肿瘤发生和治疗耐药性的三种肿瘤类型，即成神经管细胞瘤，神经胶质瘤和前列腺癌。我们预计这些肿瘤类型之间的相似性和差异，并希望所有三个交叉信息。在第一个项目中，我们将比较几种药物组合，以确定在这些肿瘤中完全阻断这种信号通路的最佳策略。第二个项目将研究在脑肿瘤和前列腺癌雄激素耗竭（去势）的情况下存活的细胞的特征，并确定PI 3 K通路在其干细胞样和抗性特性中发挥的作用。在项目3中，我们将使用这些小鼠模型来确定其他基因组改变对治疗反应的影响，并将基于mRNA的基因表达特征作为预测性生物标志物，然后将其从小鼠中用于人体试验。总的来说，这三个项目汇集了小鼠建模，实验治疗学，比较病理学和转化医学方面的专家，并为发展几位有前途的年轻医生科学家的职业生涯提供了肥沃的环境。

DESCRIPTION (provided by applicant): This application joins two physician-scientist leaders in the use of genetically engineered mouse models (GEMMs) to evaluate the utility of these animals for preclinical studies that can directly impact human clinical trials. We will investigate the biology of therapeutic response in solid tumors with particular interest in the PI3-kinase (PI3K) pathway and cells that are resistant to standard of care treatments. Based on our expertise, we will be comparing and contrasting three tumor types where the PI3K pathway contributes to oncogenesis and therapeutic resistance, namely medulloblastoma, glioma, and prostate cancer. We anticipate similarities and differences between these tumor types and expect all three to be cross-informative. In the first project we will compare several drug combinations to determine optimal strategies for complete blockade of this signaling pathway in these tumors in vivo. The second project will investigate the character of the cells that survive radiation in the case of brain tumors and androgen depletion (castration) in the case of prostate cancer, and determine what role the PI3K pathway plays in their stem-like and resistant properties. In Project 3, we will use these mouse models to determine the impact of additional genomic alterations on treatment response and identify mRNA-based gene expression signatures as predictive biomarkers that could then be taken from the mouse into human trials. Collectively, the three Projects bring together experts in mouse modeling, experimental therapeutics, comparative pathology and translational medicine and provide a fertile environment for developing the careers of several promising young physician-scientists.