Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
基本信息
- 批准号:7630446
- 负责人:
- 金额:$ 29.26万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2007
- 资助国家:美国
- 起止时间:2007-07-05 至 2012-05-31
- 项目状态:已结题
- 来源:
- 关键词:AffectApoptosisBindingBiologicalBiological AssayBiological MarkersBreastBreast Cancer CellBromodeoxyuridineCancer BiologyCancer PatientCell CycleCell NucleusCell ProliferationCellsClinicalCommunity Clinical Oncology ProgramCytoplasmDevelopmentDiagnosticElementsEpidermal Growth FactorEpidermal Growth Factor ReceptorEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorErlotinibFreezingG1 PhaseGefitinibGenetic TranscriptionGoalsGrowth Factor ReceptorsImmunoblottingIn VitroKnowledgeLuc GeneLungMalignant neoplasm of pancreasMeasuresMediatingMedical OncologistMethodsModelingMolecularMolecular BiologyMolecular Mechanisms of ActionNorthern BlottingNuclearOutcomeParaffin EmbeddingPathologistPathway interactionsPatient SelectionPatientsPatternPhasePhosphoproteinsPhosphorylationPhosphorylation SitePhosphotransferasesProtein Tyrosine KinaseProteinsReceptor SignalingRecruitment ActivityResearchResistanceRoleSamplingScanningSignal PathwaySignal TransductionSmall Interfering RNASoft Agar AssaySubgroupTechniquesThreonineTissue SampleTrainingTranslatingTyrosine Kinase InhibitorUbiquitinationWorkXenograft Modelbasecancer therapycell growthclinical efficacyclinically relevantcytotoxicitydesignexperiencehuman CDK2 proteinimprovedin vitro activityin vivoinsightknock-downmalignant breast neoplasmmutantnovelnovel therapeutic interventionoverexpressionpromoterprotein degradationprotein profilingresistance mechanismresponsetooltumor
项目摘要
DESCRIPTION (provided by applicant): The epidermal growth factor receptor (EGFR) signaling pathway is a central regulator of cell growth and proliferation and modulates critical cell cycle regulatory molecules. This pathway has emerged as a promising target for cancer therapy. EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib (Tarceva) and gefitinib (Iressa), are approved for cancer treatment but have induced a clinical response in only a subgroup of patients. Therefore, EGFR-TKI's molecular mechanism of action needs to be better understood. My long-term goal is to elucidate the molecular mechanism of action of EGFR-TKI so that novel therapeutic approaches or diagnostic tools that are clinically relevant can be developed. I have recently shown that in vitro erlotinib sensitivity is partially dependent on the activity of cyclin-dependent kinase 2 (Cdk2), which is the most downstream kinase of the EGFR pathway that regulates the transition from the G1 phase to the S phase. The objective of this application is to determine which downstream molecules of the EGFR and non-EGFR signaling pathway predict the response to EGFR-TKIs. The central hypothesis of this proposal is that the effect of Cdk2 activity on EGFR-TKI-mediated cytotoxicity is regulated by downstream molecules of the cell signaling pathway, specifically ERK, p27, and PEA15. This hypothesis is based on the following observations. First, erlotinib inhibits the tyrosine kinase of EGFR in both erlotinib-sensitive and erlotinib-resistant breast cancer cells; however, erlotinib inhibits Cdk2 activity only in sensitive cells. These findings indicate that there is an abnormality in the EGFR signaling pathway in erlotinib-resistant cells. Second, phosphorylated ERK is downregulated and p27 is upregulated in erlotinib-sensitive cells, and the phosphorylation status of p27 affects its nuclear-cytoplasmic localization and expression level. Third, PEA15 sequesters ERK into the cytoplasm from the nucleus and reduces cell proliferation. I have designed three independent but interrelated specific aims to provide a comprehensive assessment of the downstream EGFR and non-EGFR signaling pathway in breast cancer cells treated with EGFR-TKI. Specific Aim 1. Establish how erlotinib regulates p27 to suppress Cdk2 activity in vitro. Specific Aim 2. Establish how PEA15 modulates erlotinib sensitivity in vitro and in vivo. Specific Aim 3. Establish in vivo biomarkers that predict erlotinib sensitivity. Relevance: This study will provide significant insight into the role of downstream molecules affected by EGFR-TKI. Our findings will improve the outcome of cancer patients by increasing EGFR-TKI efficacy and facilitating the selection of patients who may benefit from EGFR-TKI therapy.
描述(由申请人提供):表皮生长因子受体(EGFR)信号通路是细胞生长和增殖的中心调节剂,并调节关键细胞周期调节分子。该途径已成为癌症治疗的有希望的靶标。 EGFR酪氨酸激酶抑制剂(TKIS)(例如Erlotinib(Tarceva)和Gefitinib(Iressa))被批准用于癌症治疗,但仅在患者亚组中引起了临床反应。因此,需要更好地理解EGFR-TKI的分子作用机理。我的长期目标是阐明EGFR-TKI的作用分子机制,以便可以开发出新颖的治疗方法或诊断工具。我最近表明,体外erlotinib敏感性部分取决于细胞周期蛋白依赖性激酶2(CDK2)的活性,这是EGFR途径的最下游激酶,该途径调节了从G1相向S相的过渡。该应用的目的是确定EGFR和非EGFR信号通路的哪些下游分子预测对EGFR-TKI的响应。该提议的中心假设是CDK2活性对EGFR-TKI介导的细胞毒性的影响受细胞信号通路的下游分子,特别是ERK,P27和PEA15的调节。该假设基于以下观察结果。首先,厄洛替尼抑制EGFR的酪氨酸激酶在erlotinib敏感和抗洛替尼的乳腺癌细胞中。但是,厄洛替尼仅在敏感细胞中抑制CDK2活性。这些发现表明,EGFR信号传导途径在抗洛替尼耐药细胞中存在异常。其次,磷酸化的ERK被下调,p27在erlotinib敏感的细胞中上调,P27的磷酸化状态会影响其核胞质定位和表达水平。第三,PEA15将ERK从细胞核中隔离到细胞质中,并减少细胞增殖。我设计了三个独立但相互关联的特定目的,以对用EGFR-TKI处理的乳腺癌细胞中下游EGFR和非EGFR信号通路进行全面评估。具体目标1。建立如何在体外调节p27抑制CDK2活性。具体目标2。确定PEA15在体外和体内如何调节erlotinib敏感性。特定目标3。建立预测厄洛替尼灵敏度的体内生物标志物。相关性:这项研究将为受EGFR-TKI影响的下游分子的作用提供重大见解。我们的发现将通过提高EGFR-TKI疗效并促进可能受益于EGFR-TKI治疗的患者的选择来改善癌症患者的结果。
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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Naoto T Ueno其他文献
Clinical outcomes after 1 versus 2-3 lines of neoadjuvant therapy in stage III inflammatory breast cancer.
III 期炎性乳腺癌 1 线与 2-3 线新辅助治疗后的临床结果。
- DOI:
- 发表时间:
2023 - 期刊:
- 影响因子:3.8
- 作者:
F. Nakhlis;Samuel M. Niman;Naoto T Ueno;Elizabeth Troll;Sean J. Ryan;E. Yeh;Laura Warren;J. Bellon;Beth Harrison;T. Iwase;H. T. Carisa Le;S. Saleem;M. Teshome;Gary J. Whitman;Wendy A Woodward;Beth Overmoyer;S. Tolaney;M. Regan;F. Lynce;R. Layman - 通讯作者:
R. Layman
Naoto T Ueno的其他文献
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{{ truncateString('Naoto T Ueno', 18)}}的其他基金
Developing a novel combination immunotherapy for triple-negative breast cancer
开发针对三阴性乳腺癌的新型联合免疫疗法
- 批准号:
10734197 - 财政年份:2023
- 资助金额:
$ 29.26万 - 项目类别:
Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer
开发针对炎性乳腺癌肿瘤微环境的新疗法
- 批准号:
10836263 - 财政年份:2022
- 资助金额:
$ 29.26万 - 项目类别:
Development of a novel therapy targeting the tumor microenvironment in inflammatory breast cancer
开发针对炎性乳腺癌肿瘤微环境的新疗法
- 批准号:
10390676 - 财政年份:2022
- 资助金额:
$ 29.26万 - 项目类别:
Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer
开发 PEA 15 作为卵巢癌靶向治疗基因
- 批准号:
8146139 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
- 批准号:
8265321 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer
开发 PEA 15 作为卵巢癌靶向治疗基因
- 批准号:
7500877 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
- 批准号:
7252750 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
Markers of sensivity to the EGFR inhibitor erlotinib in breast cancer
乳腺癌中 EGFR 抑制剂厄洛替尼敏感的标志物
- 批准号:
7462422 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
Development of PEA 15 as a Targeted Therapeutic Gene for Ovarian Cancer
开发 PEA 15 作为卵巢癌靶向治疗基因
- 批准号:
7894611 - 财政年份:2007
- 资助金额:
$ 29.26万 - 项目类别:
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