Novel therapeutic development for small cell lung cancer

项目总结/摘要 小细胞肺癌（SCLC）的特点是生长迅速，早期扩散， 预后Rudin实验室专注于SCLC的研究超过20年，使用完全集成的 基础发现和临床转化研究平台。我们的实验室推动了基础性的进步 对SCLC的理解和表征。我们成功地翻译了许多 我们的研究小组在临床试验中的发现，包括我们目前正在进行的许多积极的试验， 临床团队关闭循环，我们还深入从事生物标本的分子表征 接受这些新疗法的患者，以更好地告知实验室研究的新方向， 与疾病直接相关。在本R35中，我们将主要关注未来重点关注的三个主要领域， 我们的团队(1)我们实验室最近广泛的单细胞分析数据已经定义了异常的细胞内- 和原发性人SCLC的肿瘤间异质性。我们已经确定了一个关键的亚群， 能力，存在于所有SCLC亚型的肿瘤中，并且还鉴定和表征了一种新的肿瘤浸润性细胞因子。 巨噬细胞亚型仅与SCLC相关。干细胞样细胞群在24小时内逐渐扩增， 淋巴结转移和远处转移，并且该亚群的高比例赋予显著差的临床预后。 定义、表征和靶向这些新的细胞类型可能会对患有癌症的患者产生变革性影响。 SCLC。(2)我们对谱系可塑性有着长期的兴趣，包括从肺的组织学转化， 腺癌到SCLC以及SCLC亚型之间的肿瘤演变。我们现在有多种相关工具 研究肺癌谱系可塑性的生物学，包括患者来源的异种移植物（PDX） 肺腺癌模型在不同条件下转变为不同亚型的SCLC。我们将 深入分析SCLC转化的驱动因素，作为肿瘤逃逸和获得性耐药的机制， 肺癌这些数据将为预防或限制谱系可塑性作为治疗性疾病的驱动因素提供信息。 阻力(3)我们开发了一种新技术，允许在体内进行可控的CRISPR/Cas9基因编辑， PDX我们将调整该系统，使用指南在体内进行集中的SCLC遗传依赖性筛选 RNA文库覆盖可药用基因组。应用于SCLC的所有亚型，这种方法将定义 新的治疗靶点。

PROJECT SUMMARY / ABSTRACT Small cell lung cancer (SCLC) is characterized by rapid growth, early dissemination, and exceptionally poor prognosis. The Rudin laboratory has focused on the study of SCLC for over 2 decades using a fully integrated platform of basic discovery and clinical translational research. Our laboratory has driven fundamental advances in the understanding and characterization of SCLC. We have excelled in successfully translated many discoveries made by our group into clinical testing, including many active trials currently being conducted by our clinical team. Closing the circle, we are also deeply engaged in the molecular characterization of biospecimens from patients receiving these novel therapies, to better inform new directions of laboratory research while maintaining direct disease relevance. In this R35 we will focus primarily on three main areas of future focus for our group. (1) Recent extensive single cell profiling data from our laboratory has defined the exceptional intra- and inter-tumoral heterogeneity of primary human SCLC. We have identified a key subpopulation with stem-like capacity, present in tumors of all SCLC subtypes, and also identified and characterized a novel tumor-infiltrating macrophage subtype exclusively associated with SCLC. The stem-like cell population expands progressively in nodal and distant metastases, and high fraction of this subpopulation confers a strikingly poor clinical prognosis. Defining, characterizing, and targeting these novel cell types could have a transformative impact on patients with SCLC. (2) We have a long-standing interest in lineage plasticity, including histologic transformation from lung adenocarcinoma to SCLC, and tumor evolution between SCLC subtypes. We now have multiple relevant tools in hand to dissect the biology of lineage plasticity in lung cancer, including patient-derived xenograft (PDX) models of lung adenocarcinoma that under different conditions transition to different subtypes of SCLC. We will deeply analyze the drivers of SCLC transformation as a mechanism of tumor escape and acquired resistance in lung cancer. These data will inform approaches to prevent or restrict lineage plasticity as a driver of therapeutic resistance. (3) We have developed new technology allowing controlled in vivo CRISPR/Cas9 gene editing in PDX. We will adapt this system to conduct focused SCLC genetic dependency screens in vivo using a guide RNA library covering the druggable genome. Applied across all subtypes of SCLC, this approach will define novel therapeutic targets for this recalcitrant malignancy.