Genomics and Functional Characterization of NF1-mutated Lung Cancer

项目总结/摘要 摘要：肺癌是最大的癌症杀手，我们还没有针对性的治疗策略。 大多数病人然而，我们确实了解导致肺癌的基因组变化， 和不断改进的细节。NF 1基因编码RAS蛋白的负调节因子，并且经常被 在肺癌中发生突变。这一重要的大（>10%）患者亚组目前在靶向治疗中不可“操作”。 疗法这将识别和表征驱动肺形成的基因和基因组合， NF 1突变的癌症，使我们能够优先考虑这些共同驱动因素的治疗靶向。我们将使用 在相关模型中进行临床测序和功能筛选，以鉴定与NF 1合作的基因， 导致肺癌，并使用新的体内系统来验证和临床优先考虑这些目标。 背景：大约15%的患者有针对性的治疗选择，但大多数没有，尽管 事实上，我们知道有针对性的选择往往比其他选择更有效，毒性更小。我们有 表明许多肺癌携带NF 1基因突变，但这些突变不足以 在老鼠体内引发癌症。我们的目标是了解NF 1突变是如何贡献的， 其他可操作的基因组或表观基因组事件与肺腺癌形成和维持的关系， 为疾病设计新的、有针对性的选择。 方法：首先，我们将深入研究人类样本，以了解NF 1突变的克隆性， 肿瘤基因组DNA和RNA以及我们选择用于靶向治疗的患者的无细胞DNA 根据肿瘤的NF 1突变然后我们将使用最先进的功能筛选来激活 在NF 1缺失和NF 1完整的情况下内源基因的转录。最后，我们将验证 我们怀疑这些基因与NF 1缺失共同作用，在免疫活性小鼠中驱动肺腺癌。 影响：该项目关注肺癌中一种常见且研究不足的突变，肺癌是最大的癌症杀手。 世界范围内，到目前为止。每年有超过15，000名美国人死于NF 1突变的肺癌， 而没有针对他们肿瘤基因型的靶向治疗。我们将阐明NF 1突变的作用 在肺癌中起作用，并将确定与致癌二联体中NF 1丢失合作的基因。因此，这 该项目将促进开发针对新发现的癌症驱动基因的疗法， NF 1突变是我们所知道的最常见但目前不可操作的肺癌突变之一。

Project Summary/Abstract Summary: Lung cancer is the biggest cancer killer and we do not yet have targeted therapeutic strategies for most patients. We do, however, understand the genomic changes that lead to lung cancer in unprecedented and ever-improving detail. The NF1 gene encodes a negative regulator of RAS proteins, and is frequently mutated in lung cancer. This important, large (>10%) patient subset is currently not “actionable” with targeted therapy. This will identify and characterize genes and combinations of genes that drive the formation of lung cancers with NF1 mutations, enabling us to prioritize these co-drivers for therapeutic targeting. We will use clinical sequencing and functional screens in relevant models to identify genes that cooperate with NF1 to cause lung cancer, and use novel in vivo systems to validate and clinically prioritize these targets. Background: Approximately 15 percent of patients have targeted treatment options, but most do not, despite the fact that we know targeted options are often more effective and less toxic than the alternatives. We have shown that many lung cancers harbor mutations in the NF1 gene, but that these mutations are insufficient to cause cancer by themselves in the mouse. Our goal is to understand how NF1 mutations contribute, likely with other, actionable genomic or epigenomic events, to lung adenocarcinoma formation and maintenance, in order to devise new, targeted options for the disease. Methods: First we will dive deeply into human samples to understand the clonality of NF1 mutation at the levels of tumor genomic DNA, and RNA as well as cell free DNA from patients we have selected for targeted therapy based on their tumor's NF1 mutation. We will then use cutting edge functional screening to activate transcription of endogenous genes in both the NF1-deleted and NF1-intact contexts. Finally, we will validate genes that we suspect work with NF1 loss to drive lung adenocarcinoma in immunocompetent mice. Impact: This project focuses on a common and poorly-studied mutation in lung cancer, the biggest cancer killer worldwide, by far. More than 15,000 Americans die each year with NF1-mutated lung cancer, and do so without being offered targeted therapy against their tumor's genotype. We will clarify the role NF1 mutation plays in lung cancer and will identify genes that cooperate with NF1 loss in oncogenic dyads. As such, this project will foster development of therapies targeting newly identified cancer driver genes that cooperate with NF1 mutations, one of the most common, but currently not actionable, lung cancer mutations we know of.