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：
10373026
负责人：
MICHAEL C BASSIK
金额：
$ 55.26万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10373026
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 Surface Testing Therapeutic Therapeutic Intervention Time Toxic effect Treatment Efficacy Validation Work Xenograft Model advanced disease anti-cancer therapeutic base 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 lung cancer cell manufacturability mouse model neoplastic cell neutralizing antibody new therapeutic target novel overexpression patient derived xenograft model pre-clinical preclinical study receptor small hairpin RNA targeted treatment therapeutic candidate therapeutic development therapeutic evaluation therapeutically effective translational potential 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。小细胞肺癌（NSCLC）。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” “治疗肺癌的治疗策略”类别。我们先前发表的工作和广泛的工作初步数据表明CLCF1-CNTFR信号传导阻止者的阻止是独特的，以前未开发的肺癌治疗方法。 thears广泛合作以验证该信号轴，shrna遗传接近，通过发动机CNTFR受体诱饵（ECNTFR）的开发。我们将进一步发展为一种治疗性念珠菌，其热剂和蛋白水解性，免疫原性和托克斯城，可制造性和药代动力学的潜力，并将优化这些根据需要的属性。高亲和力的特征。 NSCLC的临床前模型，包括人类细胞系和患者衍生的异种移植物。进行体外生化测定，以充分定义动作作用的细胞自主机理封锁。具有良好表征的肺罐装基因工程摩托模型的模型。将允许我们在微环境上研究eCNTFR，而不是评估ECNTFR是否具有AIM 3的反态效应。加强ECNTFR疗法的组合方法通过使用专门针对FDA目标的图书馆登记的库来利用CRISPR/CAS9来公正的方式批准的药物组合疗法将在我们的研究中进行阐明该配体/受体信号轴的关键生物基础，并将提供临床前确认针对肺癌保证的企业企业策略是进一步的临床发展。