Novel therapeutic development for small cell lung cancer

项目摘要/摘要 摘要小细胞肺癌(SCLC)的特点是生长迅速、早期扩散、恶性程度极高。 预后。鲁丁实验室20多年来一直专注于小细胞肺癌的研究，使用完全集成的 基础发现和临床转化性研究平台。我们的实验室推动了根本性的进步 在对小细胞肺癌的理解和特征方面。我们已经成功地翻译了许多 我们团队在临床测试中的发现，包括我们目前正在进行的许多活跃试验 临床团队。结束这个圈子，我们也在深入研究生物旋毛虫的分子特征。 从接受这些新疗法的患者那里，更好地了解实验室研究的新方向 保持与疾病的直接相关性。在本R35中，我们将主要关注未来关注的三个主要领域 我们这群人。(1)我们实验室最近广泛的单细胞图谱数据定义了异常的内部- 原发人小细胞肺癌的瘤间异质性。我们已经确定了一个关键的亚群，具有茎状结构 容量，存在于所有小细胞肺癌亚型的肿瘤中，也发现并表征了一种新的肿瘤浸润性 巨噬细胞亚型仅与小细胞肺癌相关。干细胞样细胞的数量在 结节和远处转移，这一亚群的比例高，临床预后极差。 定义、表征和定位这些新的细胞类型可能会对患有 SCLC。(2)我们长期以来一直对谱系可塑性感兴趣，包括肺的组织学转化 腺癌向小细胞肺癌的转移，以及小细胞肺癌亚型之间的肿瘤演变。我们现在拥有多个相关工具 手部解剖肺癌的谱系可塑性生物学，包括患者来源的异种移植(PDX) 不同条件下向不同亚型小细胞肺癌转化的肺腺癌模型。我们会 深入分析小细胞肺癌转化为肿瘤逃逸和获得性耐药机制的驱动因素 肺癌。这些数据将为预防或限制谱系可塑性作为治疗驱动因素的方法提供信息 抵抗。(3)我们开发了允许体内受控CRISPR/Cas9基因编辑的新技术 PDX。我们将使用指南使该系统在活体内进行聚焦的小细胞肺癌遗传依赖性筛查 覆盖可用药基因组的RNA文库。应用于SCLC的所有子类型，此方法将定义 治疗这种顽固性恶性肿瘤的新靶点。

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.