Identification of genomic drivers of brain metastases in lung adenocarcinoma

项目摘要 50%的肺腺癌患者会发生脑转移。 患者经常发生脑转移，即使他们的颅外疾病 仍在控制之中。不幸的是，治疗方案有限，目前大多数 美国的临床试验排除了脑转移患者。我们有限的理解 脑转移的分子驱动因素阻碍了新的 治疗这种常见的癌症并发症。 我们的团队最近完成了104例脑转移瘤的全外显子组测序， 原发性肿瘤和许多组织学中的正常组织。在这个初始数据集中， 仅包括29例肺腺癌脑转移瘤，我们检测了临床 脑转移瘤特有的可操作的改变。我们现在已经 聚集了一个肺腺癌脑转移的大型队列。我们提出的 基因组分析将集中在识别和表征的分子改变， 肺腺癌脑转移我们会分析脑转移， 原发性肺肿瘤，并与未转移的肺癌进行比较。我们将 使用体外和体内转移测定来表征这些改变，包括 患者来源的异种移植物模型。这些突变的鉴定将有助于设计 更有效的治疗脑转移的方法

Project Summary Fifty percent of patients with lung adenocarcinoma will develop brain metastases. Patients frequently develop brain metastasis even while their extracranial disease remains under control. Unfortunately, treatment options are limited, and most current clinical trials in the US exclude patients with brain metastases. Our limited understanding of the molecular drivers of brain metastases has hampered the development of novel therapeutics for this common complication of cancer. Our group recently completed whole-exome sequencing of 104 brain metastases, primary tumors and normal tissue across many histologies. In this initial dataset, which included only 29 brain metastases from lung adenocarcinoma, we detected clinically actionable alterations that were unique to the brain metastases. We have now assembled a large cohort of lung adenocarcinoma brain metastases. Our proposed genomic analysis will focus on identifying and characterizing the molecular alterations in brain metastases from lung adenocarcinoma. We will analyze brain metastases and primary lung tumors and compare to lung cancers that do not metastasize. We will characterize these alterations using in vitro and in vivo assays of metastasis, including patient derived xenograft models. Identification of these mutations will aid in the design of more effective treatments for brain metastases.