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：
9767080
负责人：
JOHN D. MINNA
金额：
$ 58.69万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
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

来源：
https://reporter.nih.gov/project-details/9767080
关键词：
3-Dimensional ASCL1 gene Ablation Advocate BETA2 protein Behavior Biological Assay Biological Markers CRISPR/Cas technology Cancer Model Cancer Patient Cancer cell line Cell Line Cells ChIP-seq Chromatin Clinical Collection Congresses Data Data Set Databases Dependence Drops Drug usage Enrollment Family member Frequencies Future Genes Genetic Genetically Engineered Mouse Growth Health Human In Vitro Individual Induction of Apoptosis Knock-out Knowledge Libraries Malignant - descriptor Malignant Neoplasms Methodology Methods Modeling Molecular Molecular and Cellular Biology Mus Mutate NFIB gene Neoplasm Circulating Cells Neurosecretory Systems Oncogenes Pathogenesis Patients Pattern Pharmaceutical Preparations Pharmacology Phenotype Pre-Clinical Model Prevention approach Prevention therapy Proteins Publishing Regulator Genes Research Personnel Resistance Role Specimen Technology Testing Therapeutic Therapeutic Effect Translations Work Xenograft Model Xenograft procedure base behavior in vitro cancer survival cancer therapy cell killing clinical translation clinically translatable druggable target in vitro Assay in vivo knock-down lung small cell carcinoma mRNA Expression molecular marker neoplastic cell new therapeutic target novel therapeutics pre-clinical precision medicine predicting response predictive marker protein expression resistance frequency resistance mechanism response skills small hairpin RNA success targeted treatment therapeutic development therapy development transcription factor transcriptome sequencing tumor

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.

开发针对小细胞肺癌（SCLC）的ASCL1和NeuroD1谱系靶向治疗该应用的重点是开发针对SCLC的新靶向疗法，专注于两个关键谱系癌基因参与SCLC发病机理和恶性行为，ASCL1和Neurod1。表达ASCL1，神经1或两者兼而有之。 SCLC的基因工程小鼠模型（GEMM），表达ASCL1或NeuroD1的肿瘤出现对其表达和功能的“上瘾”。如果ASCL1/NEUROD1除去了重要的下游ONCOGEN和调节基因（通过遗传敲低）SCLC经历了许多肿瘤细胞对数。人类临床前模型，我们建议系统地研究大量SCLLC的依赖性线和Xenographs（包括患者衍生的异种移植物，PDX和循环肿瘤细胞细胞细胞衍生的饰物， CDXS）通过遗传敲低在ASCL1和NeuroD1上，并系统地测试阻断的能力遗传和药理学下游可能是trant绕因子的“可药物”靶标杀死SCLC。我们有三个特定的目标：AIM 1。临床上的SCLC模型和肿瘤标本中的临床和分子相关； ASCL1和NeuroD1遗传依赖性表型，潜在的分子生物标志物早于反应， SCLC临床前模型中的电阻的频率和机制。和Neurod1直接正规的“下游”目标作为用于治疗的漏洞使用体内定型图小型图书馆“ Dreens and Persect Press thibibit下游”的效果作为目标的“吸毒”目标。 SCLC中的治疗使用CRISPR-CAS9技术开发，包括潜在的机制阻力，我们将探索ASCL1和NeuroD1表达的可能使用生物标志物用于开发“精确医学”对这种靶向疗法的反应的“精确医学” SCLCS。组装世界上最大的临床和分子注释的人类SCLC lin和 Xengrafts以及SCLC的重要宝石，2）生成直接常规的汇编列表通过Chipseq/rNaseq和染色质景观研究的ASCL1和NeuroD1的下游靶标， 3）开发系统研究SCLC在ASCL1和和和 Neuord1下游目标。倡导者，具有成功压缩该项目的汇编技能将作为SCLC的新ASCL1和NEUROD1靶向疗法的基础。