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

基本信息

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
项目类别：
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

项目摘要

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.

概括我的实验室一直对控制癌细胞的身份和命运的机制感兴趣在肿瘤进化过程中，包括对治疗的反应。我们在这个领域做出了重要贡献过去十年的研究。我们在干细胞和癌症中视网膜母细胞瘤抑癌基因 Rb 方面的工作模型已经确定了 Rb 在控制细胞身份和可塑性方面的新功能作用，这在 Rb 突变癌细胞常常对治疗没有反应的部分原因。我们在 Rb 突变小细胞方面的开创性工作肺癌（SCLC）为这种神经内分泌癌的生物学提供了基本的新颖见解。 SCLC 是最致命的肺癌形式。治疗方案几乎没有改变过去30年。 SCLC 每年导致全球约 250,000 名患者死亡。随着全球重度吸烟者数量的增加持续增长，小细胞肺癌仍将是本世纪的一个主要健康问题。拥有独特的体内研究 SCLC 的工具以及资源丰富的合作者网络，我们处于独特的地位，可以继续对 SCLC 领域面临着很少有研究者能够解决的关键问题。重要的是，我们的研究结合了技术创新方法将使我们能够解决有关 SCLC 进展的问题使用传统的人类肿瘤来源的细胞系很难（如果不是不可能的话）进行维护，以前的小鼠模型或癌症患者样本。我们开发了快速、准确的小鼠模型人类小细胞肺癌。我们使用这些模型和患者来源的异种移植物来鉴定 SCLC 的起源细胞用于早期检测的生物标志物，以及 SCLC 致瘤表型的驱动因素及其行动机制。我们还为阐明小鼠和小鼠的基因组景观做出了贡献人类 SCLC 肿瘤。值得注意的是，我们的研究结果促成了在 SCLC 患者中实施临床试验。未来7年，我们将继续以SCLC为范式来阐明其机制确定癌细胞的身份、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代小鼠和人类肿瘤间和肿瘤内异质性方面取得的突破 SCLC 肿瘤。我们的模型是 SCLC 肿瘤具有很少的基质细胞，可以产生自己的微环境来支持它们的生长，部分是通过激活Notch信号来实现的。这种瘤内异质性可能是导致肿瘤对治疗缺乏反应的重要原因。第二个重点我们的工作是阐明 SCLC 向多个器官具有惊人转移能力的机制，包括大脑。我们建议切换到更多的神经元分化状态，伴随着神经内分泌 SCLC 细胞转移能力的获得是这种高转移潜力的一个关键方面。我们将使用独特的遗传、分子和细胞方法的组合在体内和离体测试这些想法。