Investigating molecular and cellular mechanisms of SCLC development to identify novel therapeutic strategies

研究 SCLC 发展的分子和细胞机制，以确定新的治疗策略

• 批准号: 9814560
• 负责人: JULIEN SAGE
• 金额: $ 49.02万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-09 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9814560
• 关键词: Address; Automobile Driving; Biochemical; Biology; Brain; Cancer Model; Cancer Patient; Cell Line; Cell model; Cells; Clinical Trials; Development; Evolution; Genetic; Genomic approach; Genomics; Growth; Health; Human; Laboratories; Maintenance; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular; Mus; Neoplasm Metastasis; Neuronal Differentiation; Neurosecretory Systems; Organ; Patients; Phenotype; Research; Research Personnel; Role; Sampling; Signal Transduction; Smoker; Stem cells; Stromal Cells; Testing; Tumor-Derived; Work; Xenograft procedure; cancer cell; clinical implementation; early detection biomarkers; human model; in vivo; innovation; insight; interest; lung small cell carcinoma; mouse model; mutant; notch protein; novel; novel therapeutic intervention; novel therapeutics; response; retinoblastoma tumor suppressor; tool; treatment response; tumor; tumor heterogeneity; tumor progression; tumorigenic; virtual

SUMMARY My laboratory has been interested in the mechanisms that control the identity and the fate of cancer cells during tumor evolution, including in response to treatment. We have made important contributions to this field of research in the past decade. Our work on the retinoblastoma tumor suppressor Rb in stem cells and cancer models has identified a new function role for Rb in the control of cell identity and plasticity, which explains in part why Rb-mutant cancer cells often fail to respond to therapy. Our pioneering work on Rb-mutant small cell lung cancer (SCLC) has provided fundamental novel insights into the biology of this neuroendocrine cancer. SCLC is the most lethal form of lung cancer. Treatment options have remained virtually unchanged for the past 30 years. SCLC kills ~250,000 patients worldwide every year. As the number of heavy smokers worldwide continues to grow, SCLC will remain a major health issue this century. With unique tools to study SCLC in vivo and a highly resourceful network of collaborators, we are uniquely placed to continue to greatly impact the SCLC field by confronting key issues that few investigators address. Importantly, our research combines technically innovative approaches that will allow us to address questions about SCLC progression and maintenance that are difficult, if not impossible, to tackle using traditional human tumor-derived cell lines, previous mouse models, or cancer patient samples. We have developed rapid and accurate mouse models of human SCLC. We have used these models and patient-derived xenografts to identify the cell of origin of SCLC and biomarkers for early detection, as well as drivers of the tumorigenic phenotype of SCLC and their mechanisms of action. We have also contributed to the elucidation of the genomic landscape of mouse and human SCLC tumors. Notably, our findings have led to the implementation of clinical trials in SCLC patients. In the next 7 years, we will continue to use SCLC as a paradigm to elucidate the mechanisms that determine the identity of cancer cells, their plasticity, and their fate. We will perform these studies in the context of our recent breakthroughs investigating inter- and intra-tumoral heterogeneity in primary mouse and human SCLC tumors. Our model is that SCLC tumors, which have very few stromal cells, generate their own microenvironment to support their growth, in part through activation of Notch signaling. This intra-tumoral heterogeneity may critically contribute to the lack of response of tumors to therapies. A second major focus of our work is to elucidate the mechanisms that underlie the striking metastatic ability of SCLC to multiple organs, including the brain. We propose that the switch to a more neuronal differentiation state that accompanies the gain of metastatic ability of neuroendocrine SCLC cells is a key aspect of this high metastatic potential. We will test these ideas in vivo and ex vivo using a combination of unique genetic, molecular, and cellular approaches.

总结 我的实验室一直对控制癌细胞身份和命运的机制感兴趣 在肿瘤发展过程中，包括对治疗的反应。我们在这一领域做出了重要贡献 在过去的十年里，研究。我们在干细胞和癌症中的视网膜母细胞瘤肿瘤抑制因子Rb的工作 模型已经确定了Rb在控制细胞身份和可塑性中的新功能作用，这解释了 Rb突变癌细胞通常对治疗无效的部分原因。我们在Rb突变小细胞方面的开创性工作 肺癌（SCLC）的研究为这种神经内分泌癌的生物学提供了基本的新见解。 SCLC是最致命的肺癌形式。治疗方案几乎没有变化， 过去30年SCLC每年在全球范围内杀死约25万患者。全世界的重度吸烟者人数 随着SCLC的持续增长，SCLC仍将是本世纪的主要健康问题。使用独特的工具在体内研究SCLC 和一个高度足智多谋的合作者网络，我们处于独特的地位，继续大大影响 SCLC领域面临的关键问题，很少有调查人员解决。重要的是，我们的研究结合了 技术创新的方法，使我们能够解决有关SCLC进展的问题， 使用传统的人类肿瘤衍生细胞系很难（如果不是不可能）解决维持问题， 先前的小鼠模型或癌症患者样本。我们已经开发出快速准确的小鼠模型， 人SCLC。我们已经使用这些模型和患者来源的异种移植物来鉴定SCLC的起源细胞 和用于早期检测的生物标志物，以及SCLC的致瘤表型及其 行动机制。我们还为阐明小鼠的基因组景观做出了贡献， 人SCLC肿瘤。值得注意的是，我们的研究结果导致了SCLC患者临床试验的实施。 在接下来的7年里，我们将继续使用SCLC作为范例来阐明 决定癌细胞的身份、可塑性和命运。我们将在以下背景下进行这些研究： 我们最近在研究原发性小鼠和人类肿瘤间和肿瘤内异质性方面的突破， SCLC肿瘤我们的模型是，基质细胞很少的SCLC肿瘤会产生自己的细胞 微环境来支持它们的生长，部分通过激活Notch信号传导。这种肿瘤内 异质性可能是导致肿瘤对治疗缺乏反应的关键因素。第二个重点是 我们的工作是阐明SCLC向多个器官的惊人转移能力的机制， 包括大脑。我们认为，随着神经元的分化， 获得神经内分泌SCLC细胞的转移能力是这种高转移潜力的关键方面。我们将 使用独特的遗传、分子和细胞方法的组合，在体内和体外测试这些想法。