Inhibiting VHL-positive kidney cancer
抑制 VHL 阳性肾癌
基本信息
- 批准号:8634752
- 负责人:
- 金额:$ 31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-04-01 至 2018-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAgreementApoptosisBiochemicalBiologicalBiological AssayBiological MarkersBypassCancer PatientCancer cell lineCell LineCell ProliferationCell SurvivalCellsClinicalClinical TrialsCombined Modality TherapyCytostaticsDNA biosynthesisDasatinibDiagnosticDiseaseDrug CombinationsEffector CellFocal Adhesion Kinase 1GenesGeneticGoalsGrowthHumanHypoxiaImage AnalysisImmunohistochemistryIn VitroKidneyMalignant Epithelial CellMalignant NeoplasmsMediatingMediator of activation proteinMetastatic Renal Cell CancerModelingMolecularMusMutationOncogenicOncologistOperative Surgical ProceduresOutcomePathogenesisPathway interactionsPatientsPlayProtein KinaseProtein Tyrosine KinaseProtein Tyrosine PhosphatasePublishingQuality of lifeRadiationReceptor Protein-Tyrosine KinasesRegimenRelianceRenal Cell CarcinomaRenal carcinomaReportingResearchResistanceRoleSRC geneScienceSignal PathwaySignal TransductionSpecimenStat3 proteinTherapeuticTherapeutic EffectTranslatingTumor Suppressor GenesUrogenital CancerVHL proteinValidationVascular Endothelial Growth FactorsWorkXenograft procedureangiogenesisbasecancer cellcancer therapycell transformationchemotherapyclinically relevantcytotoxicitydigital imagingeffective therapyevidence basefitnessimprovedin vivoinhibitor/antagonistinsightkillingskinase inhibitormouse modelneoplastic cellnew therapeutic targetnovelnovel therapeuticsprotein tyrosine phosphatase 1Bpublic health relevanceresponsesmall moleculesrc-Family Kinasestherapeutic targettranscription factortranslational medicinetreatment responsetumor
项目摘要
DESCRIPTION (provided by applicant): Patients with VHL-positive renal cell carcinoma (RCC) have very few treatment options. Indeed, these patients are most often told by their oncologists that experimental treatments are their best option, since there are no biologically rational treatments for them. The lack of therapeutic targets to treat VHL-positive RCC is a critical unmet need in cancer treatment. We recently demonstrated in human VHL-positive RCC cancer cells and patient tumors that the oncogenic Src kinase signaling pathway was elevated. Moreover, we found that the Src inhibitor, dasatinib reduced the proliferation of VHL-positive cells both in vitro and in mouse models. Together, our studies represent the first breakthrough for the molecularly targeted treatment of VHL-positive RCC. While dasatinib alone did slow cell proliferation, however, it failed to kill VHL-positive RCC in vitro and in vivo. We hypothesize tha the response observed with Src inhibition by dasatinib alone resulted from bypass pathways present in kidney cancer that override the therapeutic benefit of inhibiting a single target. Consistent with this possibility, VHL-positive RCC contains elevated levels of Signal Transducer and Activator of Transcription-3 (STAT3) and activated Src homology phosphotyrosine phosphatase (Shp2). Indeed, dasatinib alone failed to block oncogenic STAT3 activation. We further hypothesize that the STAT3 and Shp2 signaling pathways represent new therapeutic targets for treatment of VHL-positive RCC. This is because STAT3 plays a pivotal role in activating genes responsible for survival and chemoresistance, and Shp2 can activate downstream effectors of cell transformation in the face of Src inhibition. To address this hypothesis we will pursue the following: Aim 1: Determine the role of STAT3 in overriding Src inhibition; Aim 2: Determine the role and requirement of Shp2 signaling in VHL-positive RCC pathogenesis; and Aim 3: Identify kinase inhibitors that work synergistically with dasatinib to kil VHL-positive RCC cells. We will use human cancer cell lines and tumor specimens to establish the biological rationale for inhibiting survival and tumor-specific bypass pathways in VHL-Positive RCC and leverage this insight into novel drug combinations and biomarkers for a disease that is incurable. This proposed research, which builds on our published work, will comprehensively determine the role of transcription factors, tyrosine phosphatases and kinases in mediating resistance to Src inhibitors-and ultimately is expected to deliver more effective therapies. Importantly, this is not an incremental advance in treatment since it shifts from a reliance on monotherapy to evidence-based combination therapies that override resistance from the get-go, and thereby deliver sustained clinical responses.
描述(由申请人提供):vhl阳性肾细胞癌(RCC)患者的治疗选择很少。事实上,这些患者的肿瘤学家经常告诉他们,实验治疗是他们最好的选择,因为没有生物学上合理的治疗方法。缺乏治疗vhl阳性RCC的治疗靶点是癌症治疗中一个关键的未满足需求。我们最近在人类vhl阳性的RCC癌细胞和患者肿瘤中证实,致癌Src激酶信号通路升高。此外,我们发现Src抑制剂达沙替尼在体外和小鼠模型中都能降低vhl阳性细胞的增殖。总之,我们的研究代表了分子靶向治疗vhl阳性RCC的第一个突破。然而,单独使用达沙替尼可以减缓细胞增殖,但在体外和体内均不能杀死vhl阳性的RCC。我们假设单独使用达沙替尼抑制Src所观察到的反应是由于肾癌中存在的旁路通路,这些旁路通路覆盖了抑制单个靶点的治疗益处。与这种可能性一致的是,vhl阳性的RCC含有升高的信号换能器和转录激活因子-3 (STAT3)水平和活化的Src同源磷酸化酪氨酸磷酸酶(Shp2)。事实上,单靠达沙替尼无法阻断致癌的STAT3激活。我们进一步假设STAT3和Shp2信号通路是治疗vhl阳性RCC的新靶点。这是因为STAT3在激活负责存活和化疗耐药的基因中起着关键作用,而Shp2在Src抑制时可以激活细胞转化的下游效应物。为了解决这一假设,我们将追求以下目标:目标1:确定STAT3在压倒Src抑制中的作用;目的2:确定Shp2信号在vhl阳性RCC发病机制中的作用和要求;目标3:确定与达沙替尼协同作用以杀死vhl阳性RCC细胞的激酶抑制剂。我们将使用人类癌细胞系和肿瘤标本来建立抑制vhl阳性RCC存活和肿瘤特异性旁路通路的生物学原理,并利用这一见解来开发新的药物组合和生物标志物,以治疗这种无法治愈的疾病。这项拟议的研究基于我们已发表的工作,将全面确定转录因子、酪氨酸磷酸酶和激酶在介导Src抑制剂耐药中的作用,并最终有望提供更有效的治疗方法。重要的是,这不是治疗方面的渐进式进展,因为它从依赖单一疗法转向基于证据的联合疗法,从一开始就克服耐药性,从而提供持续的临床反应。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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George Victor Thomas其他文献
George Victor Thomas的其他文献
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{{ truncateString('George Victor Thomas', 18)}}的其他基金
Developing novel polytherapies for Non-Clear Cell Renal Cell Carcinoma
开发非透明细胞肾细胞癌的新型多疗法
- 批准号:
10555185 - 财政年份:2021
- 资助金额:
$ 31万 - 项目类别:
Developing novel polytherapies for Non-Clear Cell Renal Cell Carcinoma
开发非透明细胞肾细胞癌的新型多疗法
- 批准号:
10308505 - 财政年份:2021
- 资助金额:
$ 31万 - 项目类别:
Biospecimen Acquisition, Processing and Classification Unit
生物样本采集、处理和分类装置
- 批准号:
10005914 - 财政年份:2018
- 资助金额:
$ 31万 - 项目类别:
Biospecimen Acquisition, Processing and Classification Unit
生物样本采集、处理和分类装置
- 批准号:
10471934 - 财政年份:2018
- 资助金额:
$ 31万 - 项目类别:
Biospecimen Acquisition, Processing and Classification Unit
生物样本采集、处理和分类装置
- 批准号:
10246895 - 财政年份:2018
- 资助金额:
$ 31万 - 项目类别:
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