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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.

ASCL1和NEUROD1系癌基因靶向治疗小细胞肺癌