Multi-omic analysis of Myc-driven splicing for prostate cancer therapeutic development

Myc 驱动剪接的多组学分析用于前列腺癌治疗开发

基本信息

批准号：
10364684
负责人：
Douglas L Black
金额：
$ 63.44万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10364684
关键词：
AKT1 gene Affinity Alternative Splicing Antibodies Antibody Specificity Antigen Targeting Benign Binding Sites Bioinformatics Biological Assay Biological Models Biological Response Modifier Therapy Black race Cancer Etiology Cancer cell line Cell Culture Techniques Cell Line Cell surface Cells Cellular biology Cessation of life Chemicals Clinic Clinical Color Communities Complement Data Data Engineering Data Set Databases Development Enhancers Event Exons Family Gene Expression Profile Genes Genetic Genomic approach Genotype-Tissue Expression Project Human Immunology Immunotherapeutic agent Immunotherapy In Vitro Individual Knock-out Lead Libraries MYC Family Protein Maintenance Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Modeling Mus Neoplasm Metastasis Observational Study Oncogenes Oncogenic Pathogenesis Patients Pattern Peptides Phage Display Pharmacotherapy Phenotype Play Primary Neoplasm Program Development Prostate Prostatic Neoplasms Protein Isoforms Protein Splicing Proteins Proteomics Proto-Oncogene Proteins c-myc Proto-Oncogenes Publishing RNA Splicing RNA analysis Research Personnel Role Specificity System The Cancer Genome Atlas Therapeutic Therapeutic antibodies Tissues Transcript Validation Variant Work advanced disease antibody-dependent cell cytotoxicity anticancer research c-myc Genes cancer cell cancer genomics chimeric antigen receptor T cells combat experience experimental study genetic regulatory protein genomic data high throughput screening in vivo in vivo evaluation inhibitor interest knock-down large datasets macrophage men multiple omics neoantigens paralogous gene programs prostate cancer cell line prostate cancer model protein expression public database reconstitution screening small molecule targeted cancer therapy targeted treatment therapeutic development therapeutic target transcription factor transcriptome sequencing tumor tumor growth tumor xenograft

项目摘要

ABSTRACT We present a discovery and therapeutics development program to establish alternative splicing as a therapeutic target of Myc-driven prostate cancer. The Myc-family of proto- oncogenes, including c-Myc, N-Myc, and L-Myc, play a central role in the pathogenesis of this and many other cancers. Yet therapies inhibiting Myc action have yet to reach the clinic. As transcription factors, Myc proteins are difficult to target with either small molecules or immunotherapeutics. Indirect strategies that target downstream effectors of the Myc expression program may prove more successful. Our strategy is to target the splicing factors and alternatively spliced isoforms that the multiple Myc paralogs rely on to drive prostate cancer. Myc has been recently shown to control alternative splicing patterns that are crucial to Myc-driven tumor growth. We hypothesize that these tumors rely on specific splicing regulatory proteins that can be identified and potentially targeted with small molecules. In parallel, we hypothesize that Myc-driven alternative splicing will create cancer-specific protein isoforms suitable for immunotherapeutics development. Given the ubiquity of Myc deregulation in human cancer, we anticipate that our results will be of broad relevance to the cancer research community. We have assembled a team of investigators at UCLA with extensive experience in bioinformatics (Yi Xing), alternative splicing (Douglas Black), and cancer cell biology and immunology (Owen Witte). Our proposal integrates the analyses of cancer genomic data with focused experimental research using unique Myc-transformed human prostate materials. We will gather data on Myc-dependent alternative splicing in normal prostate tissues and primary cancers from large datasets (TCGA, GTEx) as well as datasets representing advanced disease states. Total proteomics analysis will be conducted on our transformed materials to confirm protein expression of candidate isoforms. We will employ a high-throughput screening platform developed in one of our labs to identify genetic or chemical modulators of Myc-dependent splicing events. Candidate cell surface isoforms selected for immunotherapeutics development will carry cancer- specific exon-exon junctions suitable for antibody development with phage display libraries. High-affinity, high- specificity antibodies will be built into CAR T-cells for further development

抽象的我们提出了一项发现和治疗学开发计划，以建立替代拼接作为 MYC驱动的前列腺癌的治疗靶标。原始癌基因的MYC家庭，包括C-Myc，N-Myc，和L-MYC，在该癌症和许多其他癌症的发病机理中起着核心作用。然而抑制MYC的治疗行动尚未到达诊所。作为转录因子，MYC蛋白很难用任何一个小分子或免疫治疗药。针对MYC表达的下游效应子的间接策略程序可能会更成功。我们的策略是针对多个MYC的剪接因子和剪接的同工型旁系同源物依靠前列腺癌。最近已显示MYC控制替代剪接模式对于MYC驱动的肿瘤生长至关重要。我们假设这些肿瘤依赖于特定的剪接可以鉴定并可能用小分子靶向的调节蛋白。并行，我们假设由MYC驱动的替代剪接会产生适合于癌症特异性蛋白质同工型免疫疗法开发。鉴于MYC放松管制在人类癌症中的无处不在，我们预计我们的结果将与癌症研究界具有广泛的相关性。我们已经在加州大学洛杉矶分校（UCLA）组建了一组调查员，并拥有丰富的生物信息学经验 XING），替代剪接（道格拉斯·黑）和癌细胞生物学和免疫学（Owen Witte）。我们的建议将癌症基因组数据的分析与使用独特的重点实验研究相结合 MYC转化的人类前列腺材料。我们将收集有关MYC依赖性替代剪接的数据来自大型数据集（TCGA，GTEX）以及数据集的正常前列腺组织和主要癌症代表晚期疾病状态。总蛋白质组学分析将在我们的转换上进行材料确认候选同工型的蛋白质表达。我们将采用高通量筛选在我们的一个实验室中开发的平台，以识别依赖MYC的剪接的遗传或化学调节剂事件。选择用于免疫疗法开发的候选细胞表面同工型将携带癌症 - 特定的外显子 - 外观连接适用于具有噬菌体显示库的抗体开发。高亲和力，高 - 特异性抗体将内置在汽车T细胞中以进行进一步开发