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

描述(由申请人提供)：该申请与两位内科科学家领导一起使用基因工程小鼠模型(GEMM)来评估这些动物在临床前研究中的实用性，这些研究可能直接影响人类临床试验。我们将研究实体肿瘤治疗反应的生物学，特别是对PI3K途径和耐受标准护理治疗的细胞的兴趣。基于我们的专业知识，我们将比较和对比三种类型的肿瘤，即髓母细胞瘤、胶质瘤和前列腺癌，其中PI3K通路有助于肿瘤的发生和治疗耐药。我们预测这些肿瘤类型之间的相似和不同之处，并期望所有三种肿瘤类型都具有交叉信息性。在第一个项目中，我们将比较几种药物组合，以确定在体内完全阻断这些肿瘤中这一信号通路的最佳策略。第二个项目将研究在脑肿瘤中的辐射和前列腺癌中的雄激素耗竭(去势)情况下存活的细胞的特征，并确定PI3K途径在它们的干细胞样和耐药特性中扮演什么角色。在项目3中，我们将使用这些小鼠模型来确定额外的基因组改变对治疗反应的影响，并确定基于mRNA的基因表达特征作为预测性生物标记物，然后将其从小鼠身上带入人体试验。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，并为几位有前途的年轻内科科学家的职业发展提供了肥沃的环境。

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.