Development of novel protein-based therapeutics for lung cancer

开发基于蛋白质的新型肺癌疗法

基本信息

批准号：
9894638
负责人：
MICHAEL C BASSIK
金额：
$ 56.34万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894638
关键词：
Affinity Animal Model Binding Biochemical Biological Biological Assay Biomedical Engineering Biophysics CRISPR screen CRISPR/Cas technology Cancer Etiology Cancer Model Cancer cell line Cell Surface Receptors Cells Cessation of life Characteristics Ciliary Neurotrophic Factor Ciliary Neurotrophic Factor Receptor Clinical Combined Modality Therapy Complement Complex Critical Pathways Data Development Drug Kinetics Effectiveness Engineering Etanercept FDA approved Family Fibroblasts Genetic Engineering Genetically Engineered Mouse Goals Growth Human Cell Line IL6 gene IL6ST gene In Vitro LIFR gene Laboratories Libraries Ligands MAP Kinase Gene Malignant Neoplasms Malignant neoplasm of lung Measures Mediating Modeling Non-Small-Cell Lung Carcinoma Oncogenic Outcome Patients Pharmaceutical Preparations Pharmacology Phosphorylation Pre-Clinical Model Property Protein Engineering Proteins Proteomics Publishing Receptor Signaling Role Signal Pathway Signal Transduction Structure Surface Testing Therapeutic Therapeutic Intervention Time Toxic effect Treatment Efficacy Validation Work Xenograft Model Xenograft procedure advanced disease anti-cancer therapeutic base cancer cell cancer therapy clinical development combinatorial cytokine cytokine-like factor-1 design drug candidate drug development functional genomics genetic approach immunogenicity immunoregulation in vivo innovation knock-down manufacturability mouse model neoplastic cell neutralizing antibody new therapeutic target novel overexpression pre-clinical preclinical study receptor small hairpin RNA targeted treatment therapeutic candidate therapeutic development therapeutic evaluation treatment strategy tumor tumor growth tumor progression

项目摘要

Lung cancer is the leading cause of cancer deaths worldwide. The most prevalent type of lung cancer is Non- Small Cell Lung Cancer (NSCLC). The goal of this application is to implement a collaborative effort involving preclinical models, bioengineering and functional genomics to further characterize and validate a novel “first in class” therapeutic strategy for the treatment of lung cancer. Our prior published work and extensive preliminary data indicates that blockade of CLCF1-CNTFR signaling represents a unique and previously unexplored approach for lung cancer therapy. The Sweet-Cordero and Cochran laboratories have collaborated extensively over the past several years to validate this signaling axis, first with shRNA genetic approaches, and now through the development of an engineered CNTFR receptor decoy (eCNTFR). In Aim 1, we will further develop eCNTFR as a therapeutic candidate by measuring its thermal and proteolytic stability, potential for immunogenicity and toxicity, manufacturability, and pharmacokinetics, and will optimize these properties as needed. We will also perform structural analysis of eCNTFR in complex with CLCF1 to define high affinity binding characteristics. Lastly, we will test eCNTFR for therapeutic efficacy across a wide array of preclinical models of NSCLC including human cell lines and patient-derived xenografts. In Aim 2, we will perform in vitro biochemical assays to fully define the cell-autonomous mechanism of action of eCNTFR blockade. To further understand the mechanism of action of eCNTFR in vivo, we will complement xenograft models with a well-characterized genetically engineered mouse model of lung cancer. Importantly, this model will allow us to study the effects of eCNTFR not only on tumor cells but also on the microenvironment, and to assess whether eCNTFR has immunomodulatory effects. In Aim 3, we will identify the most effective combination approaches to enhance eCNTFR therapy. These efforts will be carried out in a rational and unbiased manner by leveraging CRISPR/CAS9 using a library directed specifically at the targets of FDA approved drugs. Candidate combination therapies will then be tested in animal models. Our studies will elucidate critical biological underpinnings of this ligand/receptor signaling axis, and will provide preclinical validation of an innovative strategy for targeting lung cancer to warrant its further clinical development.

肺癌是全球癌症死亡的主要原因。最普遍的肺癌类型是非 - 小细胞肺癌（NSCLC）。该应用程序的目的是实施涉及的协作努力临床前模型，生物工程和功能基因组学，以进一步表征和验证新颖的“首先” 治疗肺癌治疗策略。我们先前发表的工作和广泛的工作初步数据表明，CLCF1-CNTFR信号的封锁代表了独特的和以前的未开发的肺癌治疗方法。甜阶和科克伦实验室有在过去的几年中，广泛合作以验证该信号轴，首先与shRNA通用接近，现在通过开发工程的CNTFR受体诱饵（ECNTFR）。在AIM 1中，我们将通过测量其热和蛋白水解稳定性，进一步发展为治疗候选者免疫原性和毒性，制造和药代动力学的潜力，并将优化这些根据需要的属性。我们还将对ECNTFR进行与CLCF1复合物的结构分析以定义高亲和力结合特征。最后，我们将测试ECNTFR的各种各样的治疗效率 NSCLC的临床前模型，包括人类细胞系和患者衍生的Xenographictics。在AIM 2中，我们将进行体外生化测定，以充分定义ECNTFR的细胞自主作用机理封锁。为了进一步了解ECNTFR在体内的作用机理，我们将完成异种移植具有良好特征的肺癌小鼠模型的模型。重要的是，这个模型将使我们不仅可以研究ECNTFR对肿瘤细胞的影响，还可以研究微环境，并研究评估ECNTFR是否具有免疫调节作用。在AIM 3中，我们将确定最有效的增强ECNTFR疗法的组合方法。这些努力将以合理的方式进行通过使用专门针对FDA目标的图书馆利用CRISPR/CAS9来利用CRISPR/CAS9来公正的方式批准的药物。然后将在动物模型中测试候选组合疗法。我们的研究将阐明该配体/受体信号轴的关键生物基础，并将提供临床前验证针对肺癌的创新策略，以保证其进一步的临床发展。