Developing ASCL1 and NeuroD1 lineage oncogene targeted therapy for small cell lung cancer

开发针对小细胞肺癌的 ASCL1 和 NeuroD1 谱系癌基因靶向治疗

基本信息

  • 批准号:
    10240702
  • 负责人:
  • 金额:
    $ 60.51万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2017
  • 资助国家:
    美国
  • 起止时间:
    2017-09-25 至 2022-08-31
  • 项目状态:
    已结题

项目摘要

Developing ASCL1 and NEUROD1 lineage oncogene targeted therapy for small cell lung cancer (SCLC) This application focuses on developing new targeted therapy for SCLC focusing on two key lineage oncogenes involved in SCLC pathogenesis and malignant behavior, ASCL1 and NEUROD1. Nearly 90% of SCLCs express ASCL1, NEUROD1 or both. In the preclinical models, including human SCLC lines and xenografts and genetically engineered mouse models (GEMMs) of SCLC, tumors that express either ASCL1 or NEUROD1 appear “addicted” to their expression and function. The presence of ASCL1 or NEUROD1 also are associated with expression of important downstream oncogenes and regulatory genes. If ASCL1/NEUROD1 are removed (through genetic knockdown) SCLCs undergo many logs of tumor cell kill. Using state of the art technology in human preclinical models, we propose to systematically study the dependency of a large number of SCLC lines and xenografts (including patient derived xenografts, PDXs, and circulating tumor cell derived xenografts, CDXs) on ASCL1 and NEUROD1 through genetic knockdown, and systematically test the ability of blocking genetically and pharmacologically downstream potentially “druggable” targets of these two transcription factors to kill SCLCs. We have three specific aims: Aim 1. Determine ASCL1 and NEUROD1 expression patterns and clinical and molecular correlates in preclinical SCLC models and tumor specimens; Aim 2. Determine ASCL1 and NEUROD1 genetic dependency phenotypes, potential molecular biomarkers predicting response, and frequency and mechanisms of resistance in SCLC preclinical models; Aim 3. Determine the role of ASCL1 and NEUROD1 directly regulated “downstream” targets as vulnerabilities that can be exploited for therapeutic effect using in vivo xenograft shRNA mini-library “drop out” screens and selected drugs that inhibit downstream “druggable” targets. As part of these aims we will also determine if resistance to ASCL1 or NEUROD1 targeted therapy in SCLCs develops using CRISPR-CAS9 technology including potential mechanisms of this resistance, and we will explore the possible use of ASCL1 and NEUROD1 expression as SCLC enrollment biomarkers for developing “precision medicine” to predict the response of such targeted therapy in individual SCLCs. We have developed a large amount of preliminary data on which this application is based including 1) assembling the world’s largest collection of clinically and molecularly annotated human SCLC lines and xenografts, as well as important GEMMs of SCLC, 2) generating a comprehensive list of directly regulated downstream targets of ASCL1 and NEUROD1 through ChipSeq/RNASeq and chromatin landscape studies, and 3) developing experimental approaches to systematically study the dependency of SCLCs on ASCL1 and NEUORD1 downstream targets. We have assembled a world class team of investigators, including a patient advocate, with complementary skills to assure the successful completion of this project. The final deliverables will serve as the basis for new ASCL1 and NEUROD1 targeted therapeutics for SCLC.
ASCL 1和NEUROD 1系癌基因靶向治疗小细胞肺癌的研究进展 该申请的重点是开发针对SCLC的新靶向治疗,重点是两个关键谱系癌基因 参与SCLC发病机制和恶性行为,ASCL 1和NEUROD 1。近90%的SCLC 表达ASCL 1、NEUROD 1或两者。在临床前模型中,包括人SCLC细胞系和异种移植物, SCLC的基因工程小鼠模型(GEMM),表达ASCL 1或NEUROD 1的肿瘤 似乎对它们的表达和功能“上瘾”。ASCL 1或NEUROD 1的存在也与 表达重要的下游癌基因和调控基因。如果ASCL 1/NEUROD 1被删除 (通过基因敲减)SCLC经历许多对数的肿瘤细胞杀伤。使用最先进的技术, 人类临床前模型,我们建议系统地研究大量SCLC的依赖性, 细胞系和异种移植物(包括患者来源的异种移植物,PDX,和循环肿瘤细胞来源的异种移植物, CDXs)对ASCL 1和NEUROD 1的基因敲除,并系统地测试阻断能力。 这两种转录因子的基因和下游潜在的“可药物化”靶点 杀死SCLC我们有三个具体目标:目标1。确定ASCL 1和NEUROD 1表达模式 以及临床前SCLC模型和肿瘤标本中的临床和分子相关性;目的2.确定 ASCL 1和NEUROD 1遗传依赖性表型,预测缓解的潜在分子生物标志物, 以及SCLC临床前模型中耐药的频率和机制;目的3.确定ASCL 1的作用 和NEUROD 1直接调节“下游”靶点,作为可用于治疗的脆弱性, 使用体内异种移植物shRNA微型文库“脱落”筛选和选择的抑制下游的药物的效果 “可下药”的目标作为这些目标的一部分,我们还将确定是否针对ASCL 1或NEUROD 1的耐药性 使用CRISPR-CAS 9技术开发SCLC治疗,包括这种治疗的潜在机制。 我们将探索ASCL 1和NEUROD 1表达作为SCLC入组的可能性 用于开发“精确医学”的生物标志物,以预测这种靶向治疗在个体中的反应。 SCLC。我们已经开发了大量的初步数据,这一应用程序的基础上,包括1) 汇集了世界上最大的临床和分子注释的人类SCLC细胞系, 异种移植物,以及SCLC的重要GEMM,2)生成直接调控的 通过ChipSeq/RNASeq和染色质横向研究, 和3)开发实验方法以系统地研究SCLC对ASCL 1的依赖性, NEUORD 1下游靶点。我们已经组建了一个世界级的调查团队,包括一个病人, 倡导,与互补的技能,以确保该项目的成功完成。最终可交付成果 将作为新的ASCL 1和NEUROD 1靶向治疗SCLC的基础。

项目成果

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JOHN D. MINNA其他文献

JOHN D. MINNA的其他文献

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{{ truncateString('JOHN D. MINNA', 18)}}的其他基金

Developing ASCL1 and NeuroD1 lineage oncogene targeted therapy for small cell lung cancer
开发针对小细胞肺癌的 ASCL1 和 NeuroD1 谱系癌基因靶向治疗
  • 批准号:
    9767080
  • 财政年份:
    2017
  • 资助金额:
    $ 60.51万
  • 项目类别:
P-1: Molecular Signatures for Individualizing Lung Cancer Therapy
P-1:个体化肺癌治疗的分子特征
  • 批准号:
    8731332
  • 财政年份:
    2013
  • 资助金额:
    $ 60.51万
  • 项目类别:
CA: Administration Core
CA:管理核心
  • 批准号:
    8731339
  • 财政年份:
    2013
  • 资助金额:
    $ 60.51万
  • 项目类别:
CA: Administration Core
CA:管理核心
  • 批准号:
    7507392
  • 财政年份:
    2008
  • 资助金额:
    $ 60.51万
  • 项目类别:
P-1: Molecular Signatures for Individualizing Lung Cancer Therapy
P-1:个体化肺癌治疗的分子特征
  • 批准号:
    7507375
  • 财政年份:
    2008
  • 资助金额:
    $ 60.51万
  • 项目类别:
Molecular Pathology of Lung Cancer
肺癌的分子病理学
  • 批准号:
    6943244
  • 财政年份:
    2005
  • 资助金额:
    $ 60.51万
  • 项目类别:
DEVELOPMENTAL RESEARCH PROGRAM
发展研究计划
  • 批准号:
    6395792
  • 财政年份:
    2000
  • 资助金额:
    $ 60.51万
  • 项目类别:
CAREER DEVELOPMENT PROGRAM
职业发展计划
  • 批准号:
    6395793
  • 财政年份:
    2000
  • 资助金额:
    $ 60.51万
  • 项目类别:
IDENTIFICATION OF 3P RECESSIVE ONCOGENES IN LUNG CANCER
肺癌中 3P 隐性癌基因的鉴定
  • 批准号:
    6395787
  • 财政年份:
    2000
  • 资助金额:
    $ 60.51万
  • 项目类别:
CAREER DEVELOPMENT PROGRAM
职业发展计划
  • 批准号:
    6217480
  • 财政年份:
    1999
  • 资助金额:
    $ 60.51万
  • 项目类别:
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