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，即使在他们的颅外疾病 仍在控制之下。不幸的是，治疗选择有限，而且最新的 在美国进行的临床试验排除了脑转移瘤患者。我们有限的理解 脑转移的分子驱动因素的研究阻碍了小说的发展 治疗这种常见的癌症并发症。 我们小组最近完成了104个脑转移瘤的全外显子组测序， 许多组织学上的原发肿瘤和正常组织。在这个初始数据集中， 仅29例肺腺癌脑转移，我们在临床上检测到 脑转移瘤特有的可操作的改变。我们现在有了 聚集了一大群肺腺癌脑转移患者。我们的建议 基因组分析将集中在鉴定和表征基因的分子变化。 肺腺癌的脑转移。我们将分析脑转移瘤和 并与不转移的肺癌进行比较。我们会 使用体外和体内转移试验来表征这些变化，包括 患者来源的异种移植模型。识别这些突变将有助于设计 对脑转移瘤进行更有效的治疗。

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.