In vivo RNAi nanoparticle cancer gene function reagent

体内RNAi纳米粒子癌基因功能试剂

基本信息

批准号：
7688089
负责人：
MARTIN C WOODLE
金额：
$ 23.54万
依托单位：
APARNA BIOSCIENCES CORPORATION
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-16 至 2011-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7688089
关键词：
A549 Address Advanced Malignant Neoplasm Animal Cancer Model Animal Disease Models Animal Model Area Biochemistry Breast Cancer Etiology Cancer Model Cancer Patient Cell Culture Techniques Cell Line Cessation of life Clinical Complex Development Diagnosis Disease Dissection Disseminated Malignant Neoplasm Drug Delivery Systems EGFR gene Effectiveness Epidermal Growth Factor Receptor Event Formalin Foundations Gene Targeting Genes Genomics Growth Head and Neck Cancer Immune In Vitro Investigation Knock-out Lasers Lesion Libraries Life Literature Malignant Neoplasms Malignant neoplasm of lung Metastatic to Methods Modeling Molecular Morphologic artifacts Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nucleic Acids Oncogenes Pathology Patients Phase Plasmids Play Primary Neoplasm Proteins Proteomics PubMed RNA Interference Reagent Reporter Research Reverse Transcriptase Polymerase Chain Reaction Role Sampling Screening procedure Small Interfering RNA Sorting - Cell Movement Structure Structure-Activity Relationship Study models TP53 gene Targeted Research Technology Testing Therapeutic Time Tissue Sample Tissues Translating Validation Xenograft Model Xenograft procedure base c-erbB-1 Proto-Oncogenes cell behavior cost effective therapy expression vector functional genomics gene function improved in vivo inhibitor/antagonist interest intravenous administration malignant breast neoplasm meetings nanoparticle neoplastic cell new therapeutic target novel plasmid DNA polypeptide public health relevance response small hairpin RNA success therapeutic target tissue fixing tumor tumor growth tumor xenograft

项目摘要

DESCRIPTION (provided by applicant): In spite of recent advances, cancer remains a major killer posing a dire need for more effective therapy, and unfortunately this is particularly true for metastatic non-small cell lung cancer (NSCLC), which afflicts an extremely large number of patients and is one of the least treatable cancers. With the growing success of targeted therapeutics, it has become clear that a greater understanding of NSCLC biochemistry and pathology is a crucial bottleneck in identifying new and better treatments. To that end considerable efforts are underway developing advanced genomic and proteomic methods applicable to clinical samples, with a major advance coming from a capability for using laser micro-dissection and protein extraction and analysis with the large libraries of formalin fixed tissue sections. However, a remaining major barrier to using this extremely valuable information for development of targeted therapeutics is to characterize the functional role of the tumor associated proteins. Yet another major advance helping address this need is the recent development of RNA interference (RNAi) but this revolutionary capability to characterize gene function has been confined largely to cell culture studies, with limited methods for in vivo administration in animal disease models such as NSCLC xenograft tumor models, and none available as a research reagent. Our hypothesis is that we can adapt our cationic polypeptide nucleic acid nanoparticle technology, which we have found effective for in vivo delivery of RNAi agents to a primary breast cancer xenograft model, for a set of metastatic and primary NSCLC xenograft tumor models. The planned research to determine feasibility of a commercializable reagent for in vivo RNAi application to metastatic and primary NSCLC xenograft tumor models has the following objectives for Phase I: 1) establish two pair of metastatic and primary NSCLC xenograft models, 2) adapt and optimize the HK polypeptide and nanoparticle structure for in vivo delivery with these models using a positive control RNAi agent, and 3) evaluate the effectiveness of the optimized HK RNAi nanoparticle for target validation using a set of candidate targets found to be differentially expressed in metastatic tumor or primary tumor lesions but not both from patient tissue samples. If successful, Phase II will undertake commercial development of a reagent for in vivo RNAi for NSCLC xenograft model gene function target validation with capabilities including metastatic cancer. PUBLIC HEALTH RELEVANCE: Metastatic non-small cell lung cancer (NSCLC) afflicts an extremely large number of patients and is one of the least treatable cancers and thus is a major area for research applying advances in genomic and proteomic methods with the objective to identify better drug targets. However, a remaining major barrier is a need for commercial reagents for using RNA interference (RNAi) directly in animal models of metastatic NSCLC. The RNAi revolutionary capability to characterize gene function and identify candidate drug targets has been confined largely to cell culture studies. Our planned studies are to adapt our cationic polypeptide nucleic acid nanoparticle technology for in vivo delivery of RNAi agents for a set of metastatic and primary NSCLC xenograft tumor models. If successful, the resulting reagent is expect to enable rapid advances in understanding this life threatening disease that produce better targeted therapeutic treatment options for patients.

描述（由申请人提供）：尽管最近进展，癌症仍然是对更有效疗法的迫切需要的主要杀手，不幸的是，对于转移性非小细胞肺癌（NSCLC）尤其如此，这会折磨大量的患者，并且是最不可治疗的癌症之一。随着目标治疗剂的成功越来越大，对NSCLC生物化学和病理学的更多了解是确定新的和更好的治疗方法的关键瓶颈。为此，正在开发适用于临床样本的先进基因组和蛋白质组学方法的巨大努力，其中很大的进步来自于使用激光微观脱落和蛋白质提取和与福尔马林固定组织的大量文库进行分析的能力。但是，将这些极为有价值的信息用于开发靶向治疗剂的剩余主要障碍是表征相关蛋白相关蛋白的功能作用。另一个有助于满足这一需求的主要进步是RNA干扰（RNAI）的最新发展（RNAI），但是这种表征基因功能的革命性能力主要局限于细胞培养研究，而在NSCLC异种移植瘤模型等动物疾病模型中，体内给药的方法有限，没有可用的研究。我们的假设是，我们可以适应阳离子多肽核酸纳米颗粒技术，这对于一组转移性和原发性NSCLC异种移植物肿瘤模型，我们发现RNAi剂在体内递送到原发性乳腺癌异种移植模型中有效。 The planned research to determine feasibility of a commercializable reagent for in vivo RNAi application to metastatic and primary NSCLC xenograft tumor models has the following objectives for Phase I: 1) establish two pair of metastatic and primary NSCLC xenograft models, 2) adapt and optimize the HK polypeptide and nanoparticle structure for in vivo delivery with these models using a positive control RNAi agent, and 3) evaluate the优化的HK RNAi纳米颗粒的有效性使用一组在转移性肿瘤或原发性肿瘤病变中差异表达的候选靶标对靶验证，但并非来自患者组织样品。如果成功，第二阶段将对NSCLC异种移植模型基因功能靶向验证（包括转移性癌症）的NSCLC异种移植模型基因功能验证的试剂进行商业开发。公共卫生相关性：转移性非小细胞肺癌（NSCLC）折磨了大量的患者，并且是最不可治疗的癌症之一，因此是研究研究基因组和蛋白质组学方法进步的主要领域，目的是确定更好的药物靶标。但是，剩余的主要障碍是直接在转移性NSCLC动物模型中使用RNA干扰（RNAi）的商业试剂。 RNAi革命性的表征基因功能和识别候选药物靶标的革命能力主要局限于细胞培养研究。我们计划的研究是为了适应我们的阳离子多肽核酸纳米粒子技术，用于在一组转移性和原发性NSCLC异种移植肿瘤模型的体内递送RNAi剂。如果成功的话，则期望由此产生的试剂能够快速进步，以了解这种威胁生命的疾病，从而为患者产生更好的靶向治疗方法。