Role of EphA2 RTK in tumor resistance to EGFR/HER2 inhibitors
EphA2 RTK 在肿瘤对 EGFR/HER2 抑制剂耐药中的作用
基本信息
- 批准号:8195840
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-10-01 至 2014-03-31
- 项目状态:已结题
- 来源:
- 关键词:AgeAntibodiesAntineoplastic AgentsBiochemicalBreastBreast AdenocarcinomaBreast Cancer CellBreast MelanomaCancer PatientCancer cell lineCause of DeathCell LineCellsClinicClinicalClinical ResearchCombined Modality TherapyComplexDataDevelopmentDiseaseDisease-Free SurvivalDrug Delivery SystemsDrug resistanceEGFR inhibitionERBB2 geneEph Family ReceptorsEphA ReceptorsEphA2 ReceptorEpidermal Growth Factor ReceptorErbB Receptor Family ProteinExhibitsFDA approvedFluorescence Resonance Energy TransferGefitinibGlioblastomaHead and Neck Squamous Cell CarcinomaHomologous GeneHumanIn VitroLaboratoriesLarge Intestine CarcinomaLinkMAP Kinase GeneMalignant NeoplasmsMediatingMolecularMonitorMonoclonal AntibodiesMouse Mammary Tumor VirusNon-Small-Cell Lung CarcinomaOncogene ErbB2Ovarian CarcinomaPathway interactionsPatientsPhosphorylationPlayPopulationPrincipal InvestigatorProstate carcinomaProtein Tyrosine KinaseRattusReporterReportingResearchResistanceRoche brand of trastuzumabRoleSeriesSignal PathwaySignal TransductionSmall Interfering RNATestingTherapeuticTransgenic ModelTrastuzumabTyrosine Kinase InhibitorUp-RegulationVascular Endothelial Growth FactorsVeteransangiogenesisbasebladder Carcinomacancer cellcancer therapycancer typedesignhuman monoclonal antibodiesin vivoinhibitor/antagonistkinase inhibitorknock-downmalignant breast neoplasmmammary epitheliummemberneoplastic cellnew therapeutic targetnoveloverexpressionpreclinical studyprogramspublic health relevancereceptor expressionresearch studyresistance mechanismrho GTP-Binding Proteinssmall moleculesuccesstumortumor initiationtumor progressiontumorigenesis
项目摘要
Project Summary/Abstract
Recent advances in the development and application of molecularly targeted therapies
for cancer have generated promising new treatments. However, a major obstacle to achieving
disease-free survival is drug resistance. The long-term objective of this research is to
investigate the mechanisms of drug resistance and target resistant tumors for treatment. This
application will specifically determine the role of EphA2 receptor tyrosine kinase in intrinsic and
acquired resistant to EGFR/HER2 inhibitors.
EGFR and HER2 belong to the ErbB family of receptor tyrosine kinases (RTKs) that are
critical for tumor initiation and metastatic progression. Several therapeutic strategies for
targeting EGFR and HER2/ErbB2 have been developed, including kinase inhibitors such as
Iressa (Gefitinib), and antibodies such as herceptin (Trastuzumab). In spite of initial efficacy,
intrinsic and acquired drug resistance is frequently observed in the clinic. We found that one of
the mechanisms of resistance to anti-EGFR/HER2 therapy is upregulation of EphA2, a member
of Eph family RTKs. EphA2 has been linked to many types of cancer, including NSCLC,
gliobastoma, melanoma, breast, colorectal, bladder, prostate and ovarian carcinomas.
Moreover, the level of EphA2 expression correlates with tumor malignancy and patient survival.
We recently reported that EphA2-deficiency impairs tumor initiation and metastatic progression
in tumors overexpressing the ErbB2 oncogene. Biochemical analyses revealed that EphA2
forms a complex with HER2 or EGFR and promotes activation of MAPK and Rho GTPase.
Additionally, MMTV-Neu tumors are sensitive to therapeutic treatment of EphA2, suggesting
that EphA2 plays an important role in HER2/EGFR-dependent tumor progression. Based on
these data, we hypothesize that overexpression of EphA2 receptor confers intrinsic and/or
acquired resistance to anti-HER2/EGFR treatment. To test this hypothesis, Specific Aim 1 will
investigate the role of EphA2 in intrinsic and acquired resistance to EGFR/HER2 inhibitors,
using a novel anti-EphA2 human monoclonal antibody. Specific Aim 2 will determine the
molecular mechanisms through which EphA2 is activated in resistant tumor cells. Together,
these studies will make significant advances towards the understanding the mechanism of drug
resistance to Her2/Erb2 based therapies. Success of this project will provide a strong rationale
for rapid clinical development of anti-EphA2 therapeutics for treatment of EGFR/HER2 resistant
tumors, which will greatly benefit the Veteran population.
项目总结/摘要
分子靶向治疗的研究进展
已经产生了有希望的新疗法。然而,实现这一目标的一个主要障碍
无病生存就是抗药性这项研究的长期目标是
探讨耐药机制和耐药肿瘤的靶点治疗。这
本申请将具体确定EphA 2受体酪氨酸激酶在内源性和内源性调节中的作用,
获得性耐EGFR/HER 2抑制剂。
EGFR和HER 2属于受体酪氨酸激酶(RTK)的ErbB家族,
对于肿瘤的发生和转移进展至关重要。几种治疗策略
已经开发了靶向EGFR和HER 2/ErbB 2的药物,包括激酶抑制剂,
易瑞沙(吉非替尼)和抗体如赫赛汀(曲妥珠单抗)。尽管最初的疗效,
在临床上经常观察到内在和获得性耐药性。我们发现,
对抗EGFR/HER 2治疗的抗性的机制是EphA 2的上调,EphA 2是EphA 2的成员,
Eph家族RTK EphA 2与许多类型的癌症有关,包括NSCLC,
胶质母细胞瘤、黑素瘤、乳腺癌、结肠直肠癌、膀胱癌、前列腺癌和卵巢癌。
此外,EphA 2表达水平与肿瘤恶性程度和患者存活率相关。
我们最近报道了EphA 2缺陷损害肿瘤的发生和转移进展,
在过度表达ErbB 2癌基因的肿瘤中。生化分析显示EphA 2
与HER 2或EGFR形成复合物并促进MAPK和Rho GT3的活化。
此外,MMTV-Neu肿瘤对EphA 2的治疗性处理敏感,表明
EphA 2在HER 2/EGFR依赖性肿瘤进展中起重要作用。基于
根据这些数据,我们假设EphA 2受体的过表达赋予了内源性和/或
对抗HER 2/EGFR治疗获得性耐药。为了验证这一假设,具体目标1将
研究EphA 2在对EGFR/HER 2抑制剂的内在和获得性抗性中的作用,
使用新的抗EphA 2人单克隆抗体。具体目标2将决定
EphA 2在抗性肿瘤细胞中被激活的分子机制。在一起,
这些研究将对理解药物的作用机制有重大的进展。
对基于Her 2/Erb 2的疗法的抗性。该项目的成功将提供强有力的理由
用于治疗EGFR/HER 2耐药的抗EphA 2治疗剂的快速临床开发
肿瘤,这将大大有利于退伍军人群体。
项目成果
期刊论文数量(0)
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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