TOR kinase inhibitors for leukemia therapy: mechanisms of action and resistance
用于白血病治疗的 TOR 激酶抑制剂:作用机制和耐药性
基本信息
- 批准号:8628792
- 负责人:
- 金额:$ 30.18万
- 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:2012-03-12 至 2017-02-28
- 项目状态:已结题
- 来源:
- 关键词:1-Phosphatidylinositol 4-KinaseActive SitesAddressAnimalsAntibodiesApoptosisApoptoticB lymphoid malignancyB-LymphocytesBCL2 geneBiological AssayBiological MarkersCCI-779Cancer PatientCause of DeathCell DeathCell LineCellsChronic Lymphocytic LeukemiaClinicalClinical TrialsComplexDataDevelopmentDrug CombinationsDrug resistanceEnzymesEquilibriumExhibitsFamily memberGene TargetingGeneticGoalsGrowthHealthHumanImatinibImmuneImmunosuppressive AgentsIn VitroJournalsKnock-outLaboratoriesLearningLinkLipidsMalignant NeoplasmsMediatingModelingMolecularMolecular Mechanisms of ActionMolecular TargetMultiprotein ComplexesMusNatureOncogenesOutputPaperPathway interactionsPharmaceutical PreparationsPhase I Clinical TrialsPhosphatidylinositolsPhosphotransferasesPhysiological ProcessesProtein KinaseProto-Oncogene Proteins c-aktRelative (related person)ResistanceRoleSignal PathwaySignal TransductionSirolimusSolid NeoplasmSystemT-LymphocyteTestingTherapeuticToxic effectTumor Cell LineTyrosine Kinase InhibitorWorkXenograft Modelbcr-abl Fusion Proteinscancer cellcancer therapycellular targetingdrug developmentdrug discoverydrug sensitivityhuman FRAP1 proteinimprovedin vivoinhibitor/antagonistkillingskinase inhibitorleukemialeukemia/lymphomaneoplastic cellnovelpre-clinicalresistance mechanismresponserituximabsmall hairpin RNAsmall moleculesuccesstooltranscription factorweapons
项目摘要
DESCRIPTION (provided by applicant): Most cancer cells display activation of phosphoinositide 3-kinase (PI3K) and the downstream enzymes AKT and TOR. Targeting the PI3K/AKT/TOR network is a promising strategy for cancer therapeutics, yet it is not clear which target profile will provide the best balance of efficacy and tolerability. Compounds that partially inhibit TOR (such as rapamycin) or compounds that inhibit both PI3K and TOR (such as PI-103) have significant limitations in efficacy and/or tolerability. A major breakthrough in this field has been the identification of novel compounds that are highly potent, selective, small molecule competitive inhibitors of TOR. Termed "active-site TOR inhibitors", these compounds fully inhibit the TOR enzyme when it is present in TORC1 or TORC2, two distinct multiprotein complexes. Compared to rapamycin, an allosteric inhibitor, active-site TOR inhibitors have a broader effect on key signaling pathways and are more effective at suppressing survival of murine and human leukemia cells. Remarkably, these compounds are less immunosuppressive than rapamycin despite their greater anti-leukemic efficacy. Active-site TOR inhibitors appear equally effective in leukemia models as the less selective PI3K/TOR inhibitors, yet are considerably better tolerated in mice. Several active-site TOR inhibitors are in early stage clinical trials. The overall objective of this proposal is to refine and extend our understanding of active-site TOR inhibitors, with the ultimate goal of improving the health of cancer patients. We will focus on B cell malignancies, since active-site TOR inhibitors have dramatic effects in B cell leukemia models yet the mechanism of action remains poorly understood. The proposal has two specific aims. First, we will establish the mechanisms by which active-site TOR inhibitors trigger leukemia cell death. In this aim we will use genetic approaches to test the hypothesis that both TORC1 and TORC2 mediate survival signaling in leukemia cells. This will be accomplished using inducible Cre-mediated knockout systems and shRNA-mediated knockdown. We will then test the roles of TORC1 and TORC2 substrates in maintaining survival in leukemia cells. Second, we will define mechanisms of cellular resistance to active-site TOR inhibitors. As with any targeted molecular approach, subtypes of cancer cells display differing sensitivity to active-site TOR inhibitors. An emerging theme in drug development is the need to identify effective combinations of targeted agents. Using cell lines that do not undergo apoptosis in response to TOR inhibition, we will use candidate and global approaches to identify druggable mechanisms of resistance. We will then test combination strategies in vitro and in vivo. Identifying mechanisms of resistance and applying appropriate drug combinations will broaden the potential application of active-site TOR inhibitors.
描述(由申请人提供):大多数癌细胞都表现出磷酸肌醇3-激酶(PI3K)和下游酶AKT和TOR的激活。针对PI3K/AKT/TOR网络是癌症治疗剂的有前途的策略,但尚不清楚哪种目标概况将提供最佳的功效和耐受性平衡。部分抑制TOR(例如雷帕霉素)或抑制PI3K和TOR(例如PI-103)的化合物在功效和/或耐受性方面具有显着限制。该领域的一个主要突破是鉴定出高度有效,选择性,小分子竞争性抑制剂的新型化合物。这些化合物称为“活跃位点TOR抑制剂”,当它存在于TORC1或TORC2中时,完全抑制了TOR酶,这是两个不同的多蛋白络合物。与雷帕霉素(一种变构抑制剂)相比,活性位点TOR抑制剂对关键信号通路具有更广泛的作用,并且在抑制鼠和人类白血病细胞的存活方面更有效。值得注意的是,尽管具有更大的抗白血病功效,但这些化合物的免疫抑制效果不如雷帕霉素。在白血病模型中,活性位点的TOR抑制剂似乎与选择性较低的PI3K/TOR抑制剂一样有效,但在小鼠中的耐受性较好。几种有源部位的TOR抑制剂正在早期临床试验中。该提案的总体目的是完善和扩展我们对主动部位抑制剂的理解,这是改善癌症患者健康状况的最终目标。我们将重点放在B细胞恶性肿瘤上,因为活跃位点的TOR抑制剂在B细胞白血病模型中具有巨大的影响,但作用机理仍然很少了解。该提案有两个具体的目标。首先,我们将建立活跃部位抑制剂引发白血病细胞死亡的机制。在此目的中,我们将使用遗传方法来检验TORC1和TORC2介导白血病细胞中存活信号的假设。这将使用可诱导的CRE介导的基因敲除系统和SHRNA介导的敲低来实现。然后,我们将测试TORC1和TORC2底物在维持白血病细胞存活中的作用。其次,我们将定义细胞对活性位点TOR抑制剂的抗性机制。与任何靶向分子方法一样,癌细胞的亚型显示出对活动点TOR抑制剂的敏感性不同。药物开发中的一个新兴主题是需要确定目标剂的有效组合。使用不响应TOR抑制的细胞系,我们将使用候选和全球方法来识别可药物的抗药性机制。然后,我们将在体外和体内测试组合策略。识别抗药性和应用适当的药物组合的机制将扩大活性位点TOR抑制剂的潜在应用。
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)
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DAVID Alexander FRUMAN其他文献
DAVID Alexander FRUMAN的其他文献
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