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:
- 金额:$ 49.02万
- 依托单位:
- 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:
- 关键词:AddressAutomobile DrivingBiochemicalBiologyBrainCancer ModelCancer PatientCell LineCell modelCellsClinical TrialsDevelopmentEvolutionGeneticGenomic approachGenomicsGrowthHealthHumanLaboratoriesMaintenanceMalignant NeoplasmsMalignant neoplasm of lungModelingMolecularMusNeoplasm MetastasisNeuronal DifferentiationNeurosecretory SystemsOrganPatientsPhenotypeResearchResearch PersonnelRoleSamplingSignal TransductionSmokerStem cellsStromal CellsTestingTumor-DerivedWorkXenograft procedurecancer cellclinical implementationearly detection biomarkershuman modelin vivoinnovationinsightinterestlung small cell carcinomamouse modelmutantnotch proteinnovelnovel therapeutic interventionnovel therapeuticsresponseretinoblastoma tumor suppressortooltreatment responsetumortumor heterogeneitytumor progressiontumorigenicvirtual
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
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每年导致全球约250,000名患者死亡。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,
使用传统的人肿瘤来源的细胞系难以(如果不是不可能的话)解决的维持,
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,SCLC肿瘤,其中有很少的基质细胞,产生自己的
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JULIEN SAGE其他文献
JULIEN SAGE的其他文献
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{{ truncateString('JULIEN SAGE', 18)}}的其他基金
Project 2: To determine the consequences of activating Rb function in cancer cells
项目 2:确定激活癌细胞中 Rb 功能的后果
- 批准号:
10597166 - 财政年份:2022
- 资助金额:
$ 49.02万 - 项目类别:
Project 2: To determine the consequences of activating Rb function in cancer cells
项目 2:确定激活癌细胞中 Rb 功能的后果
- 批准号:
10332381 - 财政年份:2022
- 资助金额:
$ 49.02万 - 项目类别:
Core A: Determining and targeting mechanisms controlling cancer cell division
核心 A:确定和靶向控制癌细胞分裂的机制
- 批准号:
10597192 - 财政年份:2022
- 资助金额:
$ 49.02万 - 项目类别:
Core A: Determining and targeting mechanisms controlling cancer cell division
核心 A:确定和靶向控制癌细胞分裂的机制
- 批准号:
10332383 - 财政年份:2022
- 资助金额:
$ 49.02万 - 项目类别:
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:
10696254 - 财政年份:2019
- 资助金额:
$ 49.02万 - 项目类别:
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:
10463652 - 财政年份:2019
- 资助金额:
$ 49.02万 - 项目类别:
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:
10013140 - 财政年份:2019
- 资助金额:
$ 49.02万 - 项目类别:
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:
10238088 - 财政年份:2019
- 资助金额:
$ 49.02万 - 项目类别:
Notch signaling in small cell lung carcinoma
小细胞肺癌中的Notch信号传导
- 批准号:
9122074 - 财政年份:2016
- 资助金额:
$ 49.02万 - 项目类别:
Molecular and cellular mechanisms of SCLC metastasis
SCLC转移的分子和细胞机制
- 批准号:
9353182 - 财政年份:2016
- 资助金额:
$ 49.02万 - 项目类别:
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