A role for c-Abl/Arg in melanoma progression
c-Abl/Arg 在黑色素瘤进展中的作用
基本信息
- 批准号:9126253
- 负责人:
- 金额:$ 30.86万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-12 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:ABL1 geneAnoikisBiochemicalBiologicalCathepsin LCathepsinsCell AdhesionCell CommunicationCell LineCell SurvivalCell-Cell AdhesionCellsClinicClinicalClinical ResearchClinical TrialsCoculture TechniquesDataDermalDetectionDevelopmentDiseaseDisease remissionDrug CombinationsDrug TargetingEndothelial CellsEnvironmentExperimental DesignsExtravasationFDA approvedFibroblastsGenetic TranscriptionGenetically Engineered MouseGoalsImatinibIn VitroLeadLungMEKsMatrix MetalloproteinasesMean Survival TimesMediatingMelanoma CellMetastatic MelanomaMolecularMouse StrainsMutationN-CadherinNME1 geneNeoplasm MetastasisOutcomePathway interactionsPatientsPeptide HydrolasesPhosphotransferasesPlayPositioning AttributePreventionProtein Tyrosine KinaseRNA InterferenceRas/RafRegimenResearchResidual stateResistanceRoleSTAT3 geneSTI571ScientistSeminalSignal PathwaySignal TransductionSolid NeoplasmStagingSurvival RateTestingTranscriptional ActivationTreatment ProtocolsUV-induced melanomaUniversitiesXenograft Modelbasec-abl Proto-Oncogeneschemotherapeutic agentdesignefficacy testinggain of functioninhibitor/antagonistinnovationinsightkillingsleukemialoss of functionmatrigelmelanomamigrationmutantnovelnovel drug combinationnovel therapeuticspreventresearch studythree dimensional cell culturetool
项目摘要
DESCRIPTION (provided by applicant): Despite 35 years of clinical trials, there has been little improvement in five-year survival rates with any chemotherapeutic regimen for the treatment of metastatic melanoma. Here, we demonstrate a previously unrecognized role for Abl kinases in melanoma cells. We found that c-Abl/Arg non-receptor tyrosine kinases are activated in primary melanomas and in melanoma cell lines, and promote proliferation, survival, cell-cell adhesion, migration, invasion, and lung colonization/metastasis. In addition, c-Abl/Arg promote matrigel invasion via STAT3 and MMP-dependent pathways; increase cell-cell adhesion; and dramatically induce degradation of a metastasis suppressor. Moreover, drugs targeting c-Abl/Arg and Raf/MEK/ERK pathways cooperate to decrease melanoma viability. Based on these novel findings, we hypothesize that c-Abl/Arg activate novel pathways that cooperate with B-Raf to promote melanoma cell-cell adhesion, migration, invasion, and metastasis. We propose a comprehensive hypothesis-driven experimental design that will establish Abl kinases as novel and exploitable drug targets for metastatic melanoma. Aim 1 will define molecular pathways by which Abl kinases promote cell-cell adhesion, migration, and invasion. To achieve our objective, we will combine biochemical, molecular, and cell biological approaches using RNAi, pharmacological inhibitors, constitutively active forms of c-Abl/Arg, rescue experiments, 2D/3D cell culture, and melanoma- endothelial co-cultures to identify migration, invasion, and cell-cell adhesion signaling pathways driven by c- Abl/Arg. Aim 2 will test the prediction that c-Abl/Arg cooperates with Abl-independent pathways (e.g. B-Raf) to promote melanoma cell-cell, adhesion, migration, and invasion. Finally, three complementary approaches will be utilized in Aim 3 to identify mechanisms by which c-Abl/Arg promote metastasis. A novel GEM model that develops metastatic UV-induced melanomas, and lung colonization and spontaneous metastasis xenograft models will be used to test the prediction that blocking c-Abl/Arg-dependent signaling pathways inhibits metastatic progression. We also will test whether B-Raf and c-Abl/Arg inhibitors cooperate to prevent metastasis of melanomas harboring B-Raf mutations. The data obtained from this proposal not only will allow us to gain insight into the fundamental mechanisms by which c-Abl/Arg drive invasion and metastasis, but also will lead to clinical studies testing the efficacy of c-Abl/Arg inhibitors for treating metastatic disease.
描述(由申请人提供):尽管进行了35年的临床试验,但对于任何化学治疗方案,用于治疗转移性黑色素瘤的五年生存率几乎没有提高。在这里,我们证明了ABL激酶在黑色素瘤细胞中的先前未识别的作用。我们发现C-ABL/ARG非受体酪氨酸激酶在原发性黑色素瘤和黑色素瘤细胞系中被激活,并促进增殖,存活,细胞细胞粘附,迁移,侵袭和肺结肠/转移。此外,C-ABL/ARG通过STAT3和MMP依赖性途径促进了矩阵侵袭。增加细胞细胞粘附;并急剧诱导转移抑制剂的降解。此外,针对C-ABL/ARG和RAF/MEK/ERK途径的药物合作可降低黑色素瘤的活力。基于这些新的发现,我们假设C-ABL/ARG激活了与B-RAF合作以促进黑色素瘤细胞粘附,迁移,入侵和转移的新型途径。我们提出了一种全面的假设驱动的实验设计,该设计将建立ABL激酶作为转移性黑色素瘤的新型和可剥削的药物靶标。 AIM 1将定义ABL激酶促进细胞 - 细胞粘附,迁移和侵袭的分子途径。为了实现我们的目标,我们将使用RNAI,药理抑制剂,C-ABL/ARG的组成型活性形式,救援实验,2D/3D细胞培养以及黑色素瘤 - 内皮培养识别迁移,入侵,入侵和细胞网络粘附c-abl cy-abl c c cy-abl c c cy- AIM 2将测试C-ABL/ARG与ABL独立途径(例如B-RAF)合作以促进黑色素瘤细胞细胞,粘附,迁移和侵袭的预测。最后,将在AIM 3中使用三种互补方法来确定C-ABL/ARG促进转移的机制。开发转移性紫外线诱导的黑色素瘤,肺定植和自发转移异种移植模型的新型宝石模型将用于测试以下预测:阻止C-ABL/ARG依赖性信号途径抑制转移性进展。我们还将测试B-RAF和C-ABL/ARG抑制剂是否合作,以防止携带B-RAF突变的黑色素瘤转移。从该提案中获得的数据不仅使我们能够深入了解C-ABL/ARG驱动侵袭和转移的基本机制,而且还将导致临床研究测试C-ABL/ARG/ARG抑制剂治疗转移性疾病的功效。
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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RINA PLATTNER其他文献
RINA PLATTNER的其他文献
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{{ truncateString('RINA PLATTNER', 18)}}的其他基金
Targeting Abl kinases in BRAF-driven melanomas
靶向 BRAF 驱动的黑色素瘤中的 Abl 激酶
- 批准号:
9762875 - 财政年份:2018
- 资助金额:
$ 30.86万 - 项目类别:
Targeting Abl kinases in BRAF-driven melanomas
靶向 BRAF 驱动的黑色素瘤中的 Abl 激酶
- 批准号:
9977973 - 财政年份:2018
- 资助金额:
$ 30.86万 - 项目类别:
Targeting Abl kinases in BRAF-driven melanomas
靶向 BRAF 驱动的黑色素瘤中的 Abl 激酶
- 批准号:
10449267 - 财政年份:2018
- 资助金额:
$ 30.86万 - 项目类别:
Targeting Abl kinases in BRAF-driven melanomas
靶向 BRAF 驱动的黑色素瘤中的 Abl 激酶
- 批准号:
10221629 - 财政年份:2018
- 资助金额:
$ 30.86万 - 项目类别:
Molecular and Cellular Oncology Research Program
分子和细胞肿瘤学研究计划
- 批准号:
10712119 - 财政年份:2013
- 资助金额:
$ 30.86万 - 项目类别:
A role for c-Abl/Arg in melanoma progression
c-Abl/Arg 在黑色素瘤进展中的作用
- 批准号:
8544438 - 财政年份:2012
- 资助金额:
$ 30.86万 - 项目类别:
A role for c-Abl/Arg in melanoma progression
c-Abl/Arg 在黑色素瘤进展中的作用
- 批准号:
8723133 - 财政年份:2012
- 资助金额:
$ 30.86万 - 项目类别:
Abl Kinases in growth factor signaling, motility, and invasion
Abl 激酶在生长因子信号传导、运动和侵袭中的作用
- 批准号:
8123233 - 财政年份:2007
- 资助金额:
$ 30.86万 - 项目类别:
KY COBRE: PDGF SIGNAL TRANSDUCTION ROLE FOR ABI FAMILY KINASES IN CELL MIGRATIO
KY COBRE:ABI 家族激酶在细胞迁移中的 PDGF 信号转导作用
- 批准号:
7610708 - 财政年份:2007
- 资助金额:
$ 30.86万 - 项目类别:
Abl kinases in growth factor signaling, motility and invasion
Abl 激酶在生长因子信号传导、运动和侵袭中的作用
- 批准号:
7305106 - 财政年份:2007
- 资助金额:
$ 30.86万 - 项目类别:
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