Credentialing Mouse Models for Immune System Therapy Research

 描述(申请人提供)：如果使用的模型(S)是对所讨论的人类疾病的准确模拟，那么使用动物模型进行临床前治疗试验是一种强有力的方法。许多研究人员使用对来自基因工程小鼠(GEM)的肿瘤的组织学评估，作为将特定的小鼠模型与已知的人类疾病亚型联系起来的一种手段。我们开发了一种基于全基因组基因表达谱的互补方法，其中我们客观地比较了来自给定器官系统(即乳房)的小鼠肿瘤的基因组图谱与人类肿瘤图谱，并已经能够识别出最能模拟人类疾病亚型的特定GEM模型。我们建议继续并扩展这些基因组验证研究，以包括更多的乳腺癌模型，并将我们的研究扩展到肺癌模型，目标是使用最合适的模型进行免疫检查点抑制剂的临床前治疗试验，因为这一领域具有巨大的临床重要性。GEM模型比其他临床前模型如PDX或人类细胞系模型更具优势，因为它们是宿主，在免疫上是完整的。我们建议研究这些GEM模型中的免疫微环境，以确定免疫逃避的机制和对最终可应用于人类临床试验的免疫检查点抑制剂的预测信号。

 DESCRIPTION (provided by applicant): The use of animal models for preclinical therapeutic testing is a powerful approach, if the model(s) used are accurate mimics of the human disease in question. Many researchers have used histological assessments of tumors coming from Genetically Engineered Mice (GEM) as a means of linking specific mouse models to known human disease subtypes. We have developed a complementary approach based upon genome-wide gene expression profiling where we objectively compare the genomic profiles of mouse tumors coming from a given organ system (i.e. breast) versus human tumor profiles, and have been able identify specific GEM models which best mimic human disease subtypes. We propose to continue and extend these genomic validation studies to include additional models of breast carcinoma and to extend our studies to models of lung cancer with the goal of using the most appropriate models for pre- clinical therapeutic trials of immune checkpoint inhibitors given the tremendous clinical importance in this area. GEM models present an advantage over other pre-clinical models like PDX or human cell line models in that they are host is immunologically intact. We propose to study the immune microenvironment in these GEM models to identify mechanisms of immune evasion and predictive signatures for response to immune checkpoint inhibitors that can ultimately be applied to human clinical trials.