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Functional Targeting of the Tyrosine Kinase EphA5 in Radiation-resistant Lung Cancer

酪氨酸激酶 EphA5 在抗辐射肺癌中的功能靶向

基本信息

批准号：
10407456
负责人：
RENATA PASQUALINI
金额：
$ 35.64万
依托单位：
RBHS -CANCER INSTITUTE OF NEW JERSEY
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：
2018-06-04 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10407456
关键词：
Address Antibodies Antibody Therapy Bacteriophages Binding Biochemical Biodistribution Biological Cell Nucleus Cells Clinical Trials Co-Immunoprecipitations Cultured Tumor Cells Cytoplasm DNA Damage DNA Repair Data Disease Drug Kinetics Exposure to G1/S Checkpoint Pathway Human Immunoglobulin G In Vitro Ionizing radiation Label Length Location Lung Neoplasms Malignant neoplasm of lung Mass Spectrum Analysis Mediating Methodology Methods Modality Modeling Molecular Monoclonal Antibodies Mus Non-Small-Cell Lung Carcinoma Outcome Patients Pharmacodynamics Phosphorylation Pre-Clinical Model Property Protein Tyrosine Kinase Proteins Proteomics Publishing Radiation Tolerance Radiation therapy Radiation-Sensitizing Agents Radiosensitization Receptor Protein-Tyrosine Kinases Recombinant Antibody Recombinants Refractory Site Stimulus Technology Testing Therapeutic Time Toxicology Translations Treatment Efficacy Treatment outcome Trypsin Work Xenograft procedure Yeasts ataxia telangiectasia mutated protein base cell growth regulation disorder control experimental study genotoxicity human monoclonal antibodies improved in vivo inhibiting antibody irradiation knock-down lung cancer cell murine monoclonal antibody neoplastic cell novel strategies phosphoproteomics preclinical development prevent radiation resistance radioresistant rational design receptor function repaired response screening small hairpin RNA success targeted imaging therapy resistant titanium dioxide translational study tumor tumor xenograft

项目摘要

Radiation therapy (RT) is an integral therapeutic modality for treating non-small cell lung cancer (NSCLC). However, lung cancer is often refractory to RT and molecular mechanisms mediating treatment resistance and tumor repopulation remain poorly defined. We have determined that the receptor tyrosine kinase EphA5 is highly expressed in lung cancer and, more importantly, its expression in patients negatively correlates with RT success and survival, thus suggesting its involvement in the regulation of cellular responses to genotoxic insult. We have assembled multiple lines of evidence to support a potential mechanism underlying EphA5-mediated radioresistance: (i) EphA5-silenced lung cancer cells display a defective G1/S cell cycle checkpoint and are unable to resolve DNA damage, (ii) upon irradiation, EphA5 is found in the nucleus of cells where it interacts with activated ataxia-telangiectasia mutated (ATM) at sites of DNA repair and, (iii) we demonstrated that a new monoclonal antibody against EphA5 sensitizes lung cancer cells and human lung cancer xenografts to RT, and significantly prolongs survival of tumor-bearing mice. In order to initiate the translation of our findings, we have developed a new methodology that utilizes in vitro and in vivo screening approaches based on phage and yeast antibody display to select and characterize antibodies with radiosensitizing properties, and capable of recognizing targets in vivo. In Aim 1, we will apply our combined hierarchical approach to generate anti-EphA5 antibodies with radiosensitizing properties and capable of targeting EphA5-expressing tumors in vivo. Aim 2 will study functions of EphA5 in DNA damage response, and how to prevent it for therapeutic purposes. Aim 3 will define biodistribution properties of selected antibodies. Toxicology studies, and exploratory pharmacodynamics/pharmacokinetics will also be performed. In Aim 4, we will test whether targeted inhibition of EphA5 combined with ionizing radiation will improve treatment outcomes.

放射治疗（RT）是治疗非小细胞肺癌（NSCLC）的一种完整的治疗方式。