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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.

总结