Targeting the Pim 1 Protein Kinase to Overcome Resistance to AKT Inhibitors
靶向 Pim 1 蛋白激酶以克服对 AKT 抑制剂的耐药性
基本信息
- 批准号:8891388
- 负责人:
- 金额:$ 31.11万
- 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:2013-09-17 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:AKT inhibitionAnimal ModelAnimalsAttentionBiochemicalCancer Cell GrowthCell Culture TechniquesCell DeathCell Surface ReceptorsCellsClinicClinicalCombined Modality TherapyComplexDataDeletion MutationDevelopmentDiseaseDisseminated Malignant NeoplasmDoseDrug TargetingDrug resistanceEffectivenessEnzymesFeedbackFibroblastsFutureGenetic EngineeringGenetically Engineered MouseGleason Grade for Prostate CancerGrowthHealthInternal Ribosome Entry SiteInvestigationLaboratoriesLeadLentivirus VectorLuciferasesMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMediatingMetabolic PathwayMetastatic Prostate CancerMusMutationNeoplasm MetastasisOutcomePIK3CA genePTEN genePathway interactionsPatientsPharmaceutical PreparationsPlayPrintingProcessProductionProstate Cancer therapyProstatic NeoplasmsProtein IsoformsProtein KinaseProtein Tyrosine KinaseProto-Oncogene Proteins c-aktReactive Oxygen SpeciesReceptor Protein-Tyrosine KinasesRegimenResearchResearch DesignResearch PersonnelResistanceResistance developmentRibosomesRoleSecondary toSignal Transduction PathwaySmall Interfering RNATranslationsUnited StatesWorkantitumor agentbasecancer initiationcell growthdesignexperiencefootimmunosuppressedinhibitor/antagonistkillingskinase inhibitorknock-downleukemiamelanomamenmouse modelnovelnovel strategiesprostate cancer cellprostate cancer cell lineproto-oncogene protein pimresearch studyresistance mechanismresponsesmall moleculesuccesstargeted treatmenttissue culturetumortumor growthtumor progression
项目摘要
DESCRIPTION (provided by applicant): The success of targeting signal transduction pathways for the development of new prostate cancer therapies has been limited to date by the subsequent development of drug resistance mechanisms. Highly activated AKT protein kinase found in almost 70% of cases of metastatic prostate cancer are an important target for therapies in this disease. Preliminary data in this proposal demonstrate that the addition of AKT inhibitors to prostate cancer cell lines induces a marked increase in cell surface receptor tyrosine kinases (RTKs) that function to limit the activity of these inhibitors in part by elevating ERK activity. Importantly, it is also demonstrated that AKT inhibitors induce the Pim-1 protein kinase, an enzyme that has been implicated in prostate cancer initiation and progression. This research team has discovered that knocking down Pim-1 either by siRNA or in genetically engineering mouse fibroblasts will inhibit the feedback in which AKT inhibitors induce RTKs. Using a small molecule Pim-1 inhibitor developed by the Kraft laboratory team, they have demonstrated that the combination of an AKT and Pim-1 inhibitor synergistically blocks prostate cancer cell growth in tissue culture, and markedly inhibits the growth of tumors in immunosuppressed animals. Data obtained suggests that AKT and Pim inhibitors regulate the translation of RTKs. These exciting findings lead to the unique hypothesis that AKT inhibitor treatment causes a Pim-1-directed feedback loop that induces RTKs that in turn stimulates increases in ERK activity. Thus, the combination of an AKT and Pim inhibitor will interrupt the induction of Pim-1 and synergize to kill prostate cancer. The specific aims in this proposal are to explore and validate this hypothesis by: 1) demonstrating in complex cell culture and animal models of prostate cancer that knocking down Pim-1 activity enhances AKT inhibitor tumor killing; 2) deciphering how AKT inhibitors increase the Pim-1 protein kinase and modulate translation to increase RTK levels; and 3) exploring how these agents can be best combined for tumor killing and to inhibit metastatic cancer, and examining whether the combination of AKT and Pim inhibitors induces a marked increase in reactive oxygen species (ROS) in prostate tumors. These studies will identify RTKs, phosphorylated ERK, and Pim-1 levels as potentially clinically important intermediate markers of AKT inhibitor action. The proposed study designs will make use of unique genetically engineered mouse models, and ribosome profiling and foot printing to explore these questions. When completed, these studies will focus attention on the potential for the development of combination therapies with Pim and AKT inhibitors to target feedback resistance mechanisms. This combination would markedly enhance responses to single agent therapies currently under investigation for the treatment of prostate cancer.
描述(由申请人提供):迄今为止,靶向信号转导通路用于开发新的前列腺癌疗法的成功受到随后耐药机制发展的限制。在几乎70%的转移性前列腺癌病例中发现的高度活化的AKT蛋白激酶是这种疾病治疗的重要靶点。该提案中的初步数据表明,向前列腺癌细胞系中添加AKT抑制剂诱导细胞表面受体酪氨酸激酶(RTK)显著增加,所述细胞表面受体酪氨酸激酶(RTK)部分地通过升高ERK活性来限制这些抑制剂的活性。重要的是,还证明了AKT抑制剂诱导Pim-1蛋白激酶,这是一种与前列腺癌发生和进展有关的酶。该研究小组发现,通过siRNA或基因工程小鼠成纤维细胞敲低Pim-1将抑制AKT抑制剂诱导RTK的反馈。使用Kraft实验室团队开发的小分子Pim-1抑制剂,他们已经证明AKT和Pim-1抑制剂的组合协同阻断组织培养中的前列腺癌细胞生长,并显着抑制免疫抑制动物中肿瘤的生长。获得的数据表明,AKT和Pim抑制剂调节RTK的翻译。这些令人兴奋的发现导致了独特的假设,即AKT抑制剂治疗引起Pim-1导向的反馈回路,其诱导RTK,进而刺激ERK活性的增加。因此,AKT和Pim抑制剂的组合将中断Pim-1的诱导并协同杀死前列腺癌。该提案的具体目的是通过以下方式探索和验证该假设:1)在复杂的细胞培养物和前列腺癌的动物模型中证明敲低Pim-1活性增强AKT抑制剂肿瘤杀伤; 2)破译AKT抑制剂如何增加Pim-1蛋白激酶并调节翻译以增加RTK水平;和3)探索这些药剂如何最好地组合用于肿瘤杀伤和抑制转移性癌症,并检查AKT和Pim抑制剂的组合是否诱导前列腺肿瘤中活性氧(ROS)的显著增加。这些研究将确定RTK、磷酸化ERK和Pim-1水平作为AKT抑制剂作用的潜在临床重要中间标志物。拟议的研究设计将利用独特的基因工程小鼠模型,核糖体分析和足迹来探索这些问题。完成后,这些研究将集中关注Pim和AKT抑制剂联合治疗的潜力,以靶向反馈耐药机制。这种组合将显著增强对目前正在研究的用于治疗前列腺癌的单药疗法的应答。
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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Andrew S Kraft其他文献
Andrew S Kraft的其他文献
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{{ truncateString('Andrew S Kraft', 18)}}的其他基金
Regulation of RNA Decapping and Degradation: A novel approach to prostate cancer therapy
RNA 脱帽和降解的调控:前列腺癌治疗的新方法
- 批准号:
10758110 - 财政年份:2023
- 资助金额:
$ 31.11万 - 项目类别:
Pim 1 Protein Kinase in Regulating Stromal Cell Biology in Prostate Cancer
Pim 1 蛋白激酶调节前列腺癌基质细胞生物学
- 批准号:
8855025 - 财政年份:2015
- 资助金额:
$ 31.11万 - 项目类别:
MUSC/HCC Paul Calabresi Clinical Oncology Training Program Plan
MUSC/HCC Paul Calabresi 临床肿瘤学培训计划计划
- 批准号:
8486908 - 财政年份:2013
- 资助金额:
$ 31.11万 - 项目类别:
Targeting the Pim 1 Protein Kinase to Overcome Resistance to AKT Inhibitors
靶向 Pim 1 蛋白激酶以克服对 AKT 抑制剂的耐药性
- 批准号:
8577635 - 财政年份:2013
- 资助金额:
$ 31.11万 - 项目类别:
Targeting the Pim 1 Protein Kinase to Overcome Resistance to AKT Inhibitors
靶向 Pim 1 蛋白激酶以克服对 AKT 抑制剂的耐药性
- 批准号:
9039263 - 财政年份:2013
- 资助金额:
$ 31.11万 - 项目类别:
Targeting the Pim 1 Protein Kinase to Overcome Resistance to AKT Inhibitors
靶向 Pim 1 蛋白激酶以克服对 AKT 抑制剂的耐药性
- 批准号:
8735893 - 财政年份:2013
- 资助金额:
$ 31.11万 - 项目类别:
Targeting the Pim 1 Protein Kinase to Overcome Resistance to AKT Inhibitors
靶向 Pim 1 蛋白激酶以克服对 AKT 抑制剂的耐药性
- 批准号:
9320825 - 财政年份:2013
- 资助金额:
$ 31.11万 - 项目类别:
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