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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。肺癌的早期症状有哪些？小细胞肺癌（NSCLC）。这个应用程序的目标是实现一个协作工作，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一种新的“首次在肺癌的治疗策略。我们先前发表的工作和广泛的初步数据表明，CLCF 1-CNTFR信号传导的阻断代表了一种独特的，肺癌的治疗方法。Sweet-Cordero和Cochran实验室在过去的几年里，他们进行了广泛的合作，以验证这一信号轴，首先是用shRNA遗传学。方法，现在通过开发工程CNTFR受体诱饵（eCNTFR）。在目标1中，我们将通过测量其热稳定性和蛋白水解稳定性来进一步开发eCNTFR作为治疗候选物，潜在的免疫原性和毒性、可制造性和药代动力学，并将优化这些所需的属性。我们还将对eCNTFR与CLCF 1的复合物进行结构分析，以确定高亲和力结合特性。最后，我们将测试eCNTFR在各种各样的治疗效果。 NSCLC的临床前模型，包括人细胞系和患者来源的异种移植物。在目标2中，我们将进行体外生化试验，以充分确定eCNTFR的细胞自主作用机制封锁为了进一步了解eCNTFR在体内的作用机制，我们将补充异种移植用一个良好表征的肺癌基因工程小鼠模型。重要的是，这种模式将使我们能够研究eCNTFR不仅对肿瘤细胞而且对微环境的影响，并评估eCNTFR是否具有免疫调节作用。在目标3中，我们将确定最有效的组合方法来增强eCNTFR治疗。这些努力将以合理和通过利用CRISPR/CAS9使用专门针对FDA目标的库，批准的药物。然后将在动物模型中测试候选组合疗法。我们的研究将阐明这种配体/受体信号传导轴的关键生物学基础，并将提供临床前验证靶向肺癌的创新策略，以保证其进一步的临床开发。