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：
10696254
负责人：
JULIEN SAGE
金额：
$ 94.33万
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/10696254
关键词：
Address Automobile Driving Biochemical Biology Brain Cancer Model Cancer Patient Cell Line Cells Development Evolution Genetic Genomic approach Genomics Growth Health Human Laboratories Maintenance Malignant neoplasm of lung Modeling Molecular Mus Neoplasm Metastasis Neuronal Differentiation Neurosecretory Systems Organ Patients Phenotype Research Research Personnel Role Sampling Signal Transduction Smoker Stromal Cells Testing Tumor-Derived Work cancer cell clinical trial implementation early detection biomarkers human model in vivo innovation insight interest lung cancer cell mouse genetics mouse model mutant neuroendocrine cancer notch protein novel novel therapeutic intervention patient derived xenograft model response retinoblastoma tumor suppressor small cell lung carcinoma stem cell model 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.

概括我的实验室对控制癌细胞的身份和命运的机制感兴趣在肿瘤演化期间，包括对治疗的响应。我们为这一领域做出了重要的贡献过去十年的研究。我们在干细胞和癌症中的视网膜细胞瘤抑制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，这在部分原因是RB突变癌细胞通常无法对治疗做出反应。我们关于RB突变小细胞的开创性工作肺癌（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是肺癌最致命的形式。治疗方案几乎保持不变过去30年。 SCLC每年在全球杀死约25万名患者。作为全世界大吸烟者的数量继续增长，SCLC将仍然是本世纪的重大健康问题。使用独特的工具来研究SCLC在体内以及一个非常机智的合作者网络，我们是独一无二的，以继续极大地影响 SCLC领域通过面对几乎没有调查人员解决的关键问题。重要的是，我们的研究结合了从技术上创新的方法，使我们能够解决有关SCLC进展和使用传统的人类肿瘤细胞系，很难（即使不是不可能）解决的维护，即使不是不可能的维护，以前的小鼠模型或癌症患者样本。我们已经开发了快速准确的鼠标模型人类SCLC。我们已经使用了这些模型和患者衍生的异种移植物来识别SCLC的起源细胞和生物标志物用于早期检测，以及SCLC肿瘤表型的驱动因素及作用机理。我们还为阐明小鼠的基因组景观做出了贡献人类SCLC肿瘤。值得注意的是，我们的发现导致在SCLC患者中实施了临床试验。在接下来的7年中，我们将继续使用SCLC作为范式来阐明这些机制确定癌细胞的身份，其可塑性和命运。我们将在上下文中进行这些研究我们最近研究原代小鼠和人类内部异质性和人体内异质性的突破 SCLC肿瘤。我们的模型是，基质细胞很少的SCLC肿瘤会产生自己的微环境可以通过激活Notch信号传导来支持其生长。这种肿瘤内异质性可能导致肿瘤对疗法的反应不足。第二个主要重点我们的工作是阐明SCLC对多个器官的惊人转移能力的机制，包括大脑。我们建议切换到伴随的更神经元分化状态神经内分泌SCLC细胞的转移性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离体中测试这些思想。