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开发计划，以建立替代剪接作为 Myc 驱动的前列腺癌的治疗靶点。原癌基因 Myc 家族，包括 c-Myc、N-Myc、和 L-Myc，在这种癌症和许多其他癌症的发病机制中发挥着核心作用。然而抑制 Myc 的疗法行动尚未到达诊所。作为转录因子，Myc 蛋白很难用小分子靶向分子或免疫疗法。针对 Myc 表达下游效应器的间接策略计划可能会更加成功。我们的策略是针对多个 Myc 的剪接因子和选择性剪接亚型旁系同源物依赖于驱动前列腺癌。 Myc 最近被证明可以控制选择性剪接模式这对于 Myc 驱动的肿瘤生长至关重要。我们假设这些肿瘤依赖于特异性剪接可以被识别并可能被小分子靶向的调节蛋白。与此同时，我们假设 Myc 驱动的选择性剪接将产生适合癌症特异性的蛋白质亚型免疫治疗的发展。鉴于 Myc 失调在人类癌症中普遍存在，我们预计我们的研究结果将与癌症研究界具有广泛的相关性。我们在加州大学洛杉矶分校组建了一支在生物信息学方面拥有丰富经验的研究人员团队（Yi Xing）、选择性剪接（Douglas Black）以及癌细胞生物学和免疫学（Owen Witte）。我们的该提案利用独特的方法将癌症基因组数据的分析与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 依赖性选择性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原发性癌症代表晚期疾病状态。将对我们的转化进行总蛋白质组学分析材料来确认候选亚型的蛋白质表达。我们将采用高通量筛选我们的一个实验室开发的平台，用于识别 Myc 依赖性剪接的遗传或化学调节剂事件。选择用于免疫治疗开发的候选细胞表面亚型将携带癌症- 适合使用噬菌体展示文库进行抗体开发的特定外显子-外显子连接。高亲和力、高特异性抗体将被内置到 CAR T 细胞中以供进一步开发