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:
- 金额:$ 35.64万
- 依托单位:
- 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:
- 关键词:AddressAntibodiesAntibody TherapyBacteriophagesBindingBiochemicalBiodistributionBiologicalCell NucleusCellsClinical TrialsCo-ImmunoprecipitationsCultured Tumor CellsCytoplasmDNA DamageDNA RepairDataDiseaseDrug KineticsExposure toG1/S Checkpoint PathwayHumanImmunoglobulin GIn VitroIonizing radiationLabelLengthLocationLung NeoplasmsMalignant neoplasm of lungMass Spectrum AnalysisMediatingMethodologyMethodsModalityModelingMolecularMonoclonal AntibodiesMusNon-Small-Cell Lung CarcinomaOutcomePatientsPharmacodynamicsPhosphorylationPre-Clinical ModelPropertyProtein Tyrosine KinaseProteinsProteomicsPublishingRadiation ToleranceRadiation therapyRadiation-Sensitizing AgentsRadiosensitizationReceptor Protein-Tyrosine KinasesRecombinant AntibodyRecombinantsRefractorySiteStimulusTechnologyTestingTherapeuticTimeToxicologyTranslationsTreatment EfficacyTreatment outcomeTrypsinWorkXenograft procedureYeastsataxia telangiectasia mutated proteinbasecell growth regulationdisorder controlexperimental studygenotoxicityhuman monoclonal antibodiesimprovedin vivoinhibiting antibodyirradiationknock-downlung cancer cellmurine monoclonal antibodyneoplastic cellnovel strategiesphosphoproteomicspreclinical developmentpreventradiation resistanceradioresistantrational designreceptor functionrepairedresponsescreeningsmall hairpin RNAsuccesstargeted imagingtherapy resistanttitanium dioxidetranslational studytumortumor 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。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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RENATA PASQUALINI的其他文献
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{{ truncateString('RENATA PASQUALINI', 18)}}的其他基金
High-throughput Screenings to Identify Host Receptors for Staphylococcal Adhesins
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- 资助金额:
$ 35.64万 - 项目类别:
High-throughput Screenings to Identify Host Receptors for Staphylococcal Adhesins
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8271409 - 财政年份:2009
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Targeted Modulation of Angiogenesis by VEGFR Peptidomimetic Antagonists
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8752696 - 财政年份:2009
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Targeted Modulation of Angiogenesis by VEGFR Peptidomimetic Antagonists
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- 资助金额:
$ 35.64万 - 项目类别:
Targeted Modulation of Angiogenesis by VEGFR Peptidomimetic Antagonists
VEGFR 肽模拟拮抗剂对血管生成的靶向调节
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$ 35.64万 - 项目类别:
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血管基因组学和蛋白质组学的整合在癌症诊断和治疗中的应用
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7684579 - 财政年份:2008
- 资助金额:
$ 35.64万 - 项目类别:
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