Targeting Wnt/Ca2+ Pathway components and Bcr-Abl for the treatment of CML
靶向 Wnt/Ca2 通路成分和 Bcr-Abl 治疗 CML
基本信息
- 批准号:8099671
- 负责人:
- 金额:$ 11.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2012-06-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaBiologicalCalcineurinCalciumCalcium SignalingCellsChromosomes, Human, Pair 22Chronic Myeloid LeukemiaChronic-Phase Myeloid LeukemiaCombined Modality TherapyDevelopmentDiseaseExposure toGene ComponentsGene TargetingGenesGenetic TranscriptionGleevecImatinibImatinib mesylateIn VitroLeadLeukemic CellMediatingMediator of activation proteinMicroarray AnalysisModelingOncogenicPathway interactionsPhiladelphia ChromosomeProductionProtein Tyrosine KinaseProteinsRNA InterferenceRNA libraryRefractoryRelapseResistanceRoleSignal PathwayTherapeuticTyrosine Kinase Inhibitorbcr-abl Fusion Proteinscalmodulin-dependent protein kinase IIcancer typecell killingdesigngenome-widein vivoinhibitor/antagonistkillingsleukemialoss of functionmouse modelnovelresponsesmall hairpin RNAsmall moleculetreatment strategy
项目摘要
DESCRIPTION (provided by applicant): Chronic myeloid leukemia (CML) and about 20% of acute lymphoblastic leukemias (ALL) are characterized by expression of the oncogenic fusion protein Bcr-Abl that has constitutive tyrosine kinase activity. The selective Bcr-Abl antagonist imatinib mesylate (Gleevec) is a small molecule tyrosine kinase inhibitor that has proven highly effective in the treatment of CML. Although effective, imatinib therapy is usually not curative. Imatinib fails to completely eliminate Bcr-Abl+ cells and the disease often relapses due to development of imatinib resistance. Also, Bcr-Abl+ ALL is refractory to treatment with imatinib. Targeting additional gene products may enhance the efficacy of imatinib in eliminating CML and Bcr-Abl+ ALL cells and lead to complete eradication of disease. We have designed an unbiased loss-of-function screen using RNA interference (RNAi) to identify such genes. We utilized a genome-wide lentiviral small hairpin RNA (shRNA) library in combination with microarray analysis to identify gene targets that, when inhibited, potentiate Bcr-Abl+ cell killing by imatinib. Our screen identified multiple genes that are components of a noncanonical Wnt/calcium signaling pathway whose biological role is poorly understood. We plan to further analyze these genes to determine if their inactivation effectively cooperates with imatinib in killing Bcr-Abl+ cells in vitro and in mouse models of CML and Bcr-Abl+ ALL.
描述(由申请人提供):慢性髓性白血病(CML)和约20%的急性淋巴细胞白血病(ALL)的特征在于具有组成型酪氨酸激酶活性的致癌融合蛋白Bcr-Abl的表达。选择性Bcr-Abl拮抗剂甲磺酸伊马替尼(格列卫)是一种小分子酪氨酸激酶抑制剂,已被证明在治疗CML中非常有效。尽管伊马替尼治疗有效,但通常无法治愈。伊马替尼不能完全消除Bcr-Abl+细胞,并且由于伊马替尼耐药性的发展,疾病经常复发。此外,Bcr-Abl+ ALL对伊马替尼治疗难治。靶向其他基因产物可能会增强伊马替尼消除CML和Bcr-Abl+ ALL细胞的疗效,并导致疾病的完全根除。我们设计了一个无偏见的功能丧失筛选使用RNA干扰(RNAi)来识别这些基因。我们利用全基因组慢病毒小发夹RNA(shRNA)文库结合微阵列分析,以确定基因靶点,当被抑制时,增强伊马替尼对Bcr-Abl+细胞的杀伤。我们的筛选鉴定了多个基因,它们是非经典Wnt/钙信号通路的组成部分,其生物学作用知之甚少。我们计划进一步分析这些基因,以确定它们的失活是否有效地协同伊马替尼在体外和CML和Bcr-Abl+ ALL小鼠模型中杀死Bcr-Abl+细胞。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Using functional genomics to overcome therapeutic resistance in hematological malignancies.
- DOI:10.1007/s12026-012-8353-z
- 发表时间:2013-03
- 期刊:
- 影响因子:4.4
- 作者:Alvarez-Calderon, Francesca;Gregory, Mark A.;DeGregori, James
- 通讯作者:DeGregori, James
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{{ truncateString('MARK A GREGORY', 18)}}的其他基金
Targeting an ATM-dependent metabolic pathway and FLT3 for AML therapy
针对 AML 治疗的 ATM 依赖性代谢途径和 FLT3
- 批准号:
8425909 - 财政年份:2012
- 资助金额:
$ 11.52万 - 项目类别:
Targeting an ATM-dependent metabolic pathway and FLT3 for AML therapy
针对 AML 治疗的 ATM 依赖性代谢途径和 FLT3
- 批准号:
8541799 - 财政年份:2012
- 资助金额:
$ 11.52万 - 项目类别:
Targeting Wnt/Ca2+ Pathway components and Bcr-Abl for the treatment of CML
靶向 Wnt/Ca2 通路成分和 Bcr-Abl 治疗 CML
- 批准号:
7659826 - 财政年份:2009
- 资助金额:
$ 11.52万 - 项目类别:
Targeting Wnt/Ca2+ Pathway components and Bcr-Abl for the treatment of CML
靶向 Wnt/Ca2 通路成分和 Bcr-Abl 治疗 CML
- 批准号:
7869445 - 财政年份:2009
- 资助金额:
$ 11.52万 - 项目类别:
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