Validating Syk as a Target for AML Therapy
验证 Syk 作为 AML 治疗靶点
基本信息
- 批准号:8296670
- 负责人:
- 金额:$ 35.22万
- 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:2009-07-07 至 2014-04-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAML1-ETO fusion proteinAcute Myelocytic LeukemiaAcute Promyelocytic LeukemiaAddressApoptosisAutoimmune DiseasesB cell differentiationB-Cell LymphomasBiochemicalBiochemical GeneticsBiologicalBiological AssayBlast CellBone MarrowCell DeathCell LineCell SurvivalCell surfaceCellsCessation of lifeChemotherapy-Oncologic ProcedureClinicalClinical TrialsComplementary DNAComplexCytotoxic ChemotherapyDataDefectDevelopmentDifferentiation InducerDiseaseDoseDysmyelopoietic SyndromesEpidermal Growth FactorEpidermal Growth Factor ReceptorFlow CytometryGefitinibGene ExpressionGene Expression ProfileGeneticGenomicsGoalsGrantHematologic NeoplasmsHematopoieticHumanIn VitroLaboratoriesLeadLiteratureLymphomaMAP Kinase GeneMeasurementMeasuresModelingMutagenesisMyelogenousMyeloid CellsPI3K/AKTPathogenesisPathologyPathway interactionsPatientsPeripheralPharmaceutical PreparationsPharmacodynamicsPharmacologic SubstancePhasePhenotypePhosphorylationPhosphotransferasesPilot ProjectsPositioning AttributePreclinical TestingProdrugsProtein Tyrosine KinaseProteinsProteomicsRNA InterferenceReceptor SignalingReceptors, Antigen, B-CellRefractoryRelapseReportingSTAT5A geneScreening procedureSignal TransductionSiteSpleenStagingT-Cell LymphomaTestingTherapeuticTimeTranslationsTretinoinTyrosine Kinase InhibitorWeightWorkXenograft procedurebasecell growthgenome-widehigh throughput screeninghuman SYK proteinin vivoin vivo Modelinhibitor/antagonistmutantpreclinical studyresearch studysmall hairpin RNAsmall moleculetooltranscription factor
项目摘要
PROJECT ABSTRACT
Little progress has been made in the treatment of acute myeloid leukemia (AML) despite dose intensification of
cytotoxic chemotherapy. An alternative approach to treating AML is the incorporation of pro-differentiation
agents into standard chemotherapy regimens. In order to identify new AML differentiation agents, our
laboratory developed a gene expression-based approach to small molecule screening. We identified gefitinib,
an epidermal growth factor (EGFR) inhibitor, as an inducer of AML differentiation. EGFR is not expressed in
the tested AML cell lines, thus precluding inhibition of this kinase as the mechanism of AML differentiation.
Because multiple EGFR inhibitors induce the phenotype, we hypothesize that a shared off-target kinase is the
target in AML differentiation. In order to identify candidate gefitinib targets of AML differentiation, we utilized
proteomic and genetic approaches. Spleen tyrosine kinase (Syk) was identified as the top candidate. Syk is a
nonreceptor tyrosine kinase, important in normal B-cell differentiation, and implicated in hematological
malignancies. We hypothesize that Syk is a target for AML therapy and that loss of Syk will result in
differentiation and/or cell death in AML. We confirmed with both pharmacological inhibition (R406) and genetic
loss of Syk the induction of differentiation and/or death in a pilot study of AML cells. We now propose to more
broadly test this hypothesis with the following Specific Aims.
Specific Aim 1. Characterize the in vitro and in vivo effects of R406 in AML
Specific Aim 2. Establish that Syk is the target of R406 activity in AML
Specific Aim 3. Determine the downstream effectors of Syk in AML
In Aim 1, we will determine the broad potential of Syk inhibition as an anti-AML therapy. We will measure the in
vitro effects of a Syk inhibitor (R406) in a large panel of AML cells on differentiation, cell growth, and apoptosis.
We will then extend testing to in vivo studies using primary human AML orthotopic models. Next, in Aim 2, we
will confirm that Syk is the target of R406 activity with three parallel approaches: A PCR mutagenesis screen
for Syk mutants that rescue the effects of R406 anti-AML activity; a genetic approach using RNA interference,
and a pharmacological approach evaluating other small molecule inhibitors of Syk. In Aim 3, we will determine
which proteins are critical downstream effectors of Syk signaling in AML using complementary approaches:
biochemical, genetic, genomic, pharmacological, and proteomic. The Rigel Pharmaceutical compound, R788,
the prodrug of R406, is already in Phase II testing and was recently demonstrated to have activity in
autoimmune disease and lymphoma. With Phase I testing now complete and efficacy demonstrated for these
diseases, we would be well positioned to rapidly bring R788 to clinical trial. These studies, within the five
year time frame of this grant, will have immediate translational relevance and inform the development
of a clinical trial testing Syk inhibition in patients with relapsed/refractory AML.
项目摘要
在急性髓性白血病(AML)的治疗中几乎没有进展,尽管使用了剂量强化的化疗。
细胞毒化疗治疗急性粒细胞白血病的另一种方法是结合促分化
药物进入标准化疗方案。为了鉴定新的AML分化剂,我们的
实验室开发了一种基于基因表达的小分子筛选方法。我们发现了吉非替尼,
表皮生长因子(EGFR)抑制剂,作为AML分化的诱导剂。EGFR不表达于
所测试的AML细胞系,从而排除了作为AML分化机制的该激酶的抑制。
由于多种EGFR抑制剂诱导表型,我们假设一个共同的脱靶激酶是
AML分化的靶点。为了鉴定AML分化的候选吉非替尼靶点,我们利用
蛋白质组学和遗传学方法。脾酪氨酸激酶(Syk)被确定为最佳候选者。Syk是一个
非受体酪氨酸激酶,在正常B细胞分化中很重要,并与血液学
恶性肿瘤我们假设Syk是AML治疗的靶点,Syk的缺失将导致
在AML中的分化和/或细胞死亡。我们证实了药理学抑制(R406)和遗传学抑制(R406)。
在AML细胞的初步研究中,Syk的丧失诱导分化和/或死亡。我们现在建议更多
用以下具体目标来广泛地检验这一假设。
具体目标1。表征R406在AML中的体外和体内作用
具体目标2。确定Syk是AML中R406活性的靶点
具体目标3。确定AML中Syk的下游效应物
在目标1中,我们将确定Syk抑制作为抗AML治疗的广泛潜力。我们将测量
Syk抑制剂(R406)在一大组AML细胞中对分化、细胞生长和凋亡的体外作用。
然后,我们将使用原代人AML原位模型将测试扩展到体内研究。在目标2中,我们
将用三种平行方法证实Syk是R406活性的靶标:PCR诱变筛选
对于拯救R406抗AML活性效果的Syk突变体;使用RNA干扰的遗传方法,
以及评价Syk的其他小分子抑制剂的药理学方法。在目标3中,我们将确定
哪些蛋白质是使用互补方法的AML中Syk信号传导的关键下游效应物:
生物化学、遗传学、基因组学、药理学和蛋白质组学。参宿七制药的化合物R788
R406的前体药物,已经在II期试验中,最近被证明具有以下活性:
自身免疫性疾病和淋巴瘤。随着I期试验的完成和疗效的证明,这些
因此,我们将有能力迅速将R788投入临床试验。这些研究中,
这项赠款的一年时间框架,将有直接的翻译相关性,并告知发展
在复发/难治性AML患者中测试Syk抑制的临床试验。
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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Kimberly Stegmaier其他文献
Kimberly Stegmaier的其他文献
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Dissecting the Pathogenesis of Ewing Sarcoma with Integrative Genomics
用综合基因组学剖析尤文肉瘤的发病机制
- 批准号:
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- 资助金额:
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Integrating Transforming Approaches to Identify and Target New Vulnerabilities in Cancer
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