Targeting PTPN11 dependent Hematologic Malignancies
靶向 PTPN11 依赖性血液恶性肿瘤
基本信息
- 批准号:10520047
- 负责人:
- 金额:$ 34.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-12-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:Acute Myelocytic LeukemiaAdaptor Signaling ProteinAddressAnimal ModelBiochemicalBiochemical PathwayBiological AssayBiological ModelsBone Marrow CellsCRISPR/Cas technologyCell LineCell SurvivalCell modelCellsChemicalsChemoresistanceClinicalCombined Modality TherapyComplexDataDependenceDevelopmentDiseaseDrug CombinationsEvaluationFoundationsGoalsHematologic NeoplasmsHematologyHematopoieticImmunodeficient MouseIn VitroJuvenile Myelomonocytic LeukemiaKnowledgeLeukemic CellMAP Kinase GeneMAPK Signaling Pathway PathwayMEKsMalignant NeoplasmsModelingMolecularMusMutationPTPN11 genePathogenesisPathway interactionsPatientsPhosphorylationPhosphotransferasesPlayPrognosisProliferatingProtein DephosphorylationProtein Tyrosine KinaseProtein Tyrosine PhosphataseProteinsRNA InterferenceRoleSamplingSignal TransductionSolid NeoplasmTertiary Protein StructureTestingTherapeuticTransduction GeneTransgenic OrganismsTreatment ProtocolsValidationXenograft procedureacute myeloid leukemia cellcell killingclinical developmenteffective therapyexperienceimprovedin vivoinhibitorleukemiamouse modelmutantneoplastic cellnovelpre-clinicalprotein complexprotein phosphatase inhibitor-2responsesmall molecule inhibitortargeted treatmenttherapeutic target
项目摘要
Activating mutations in Protein Tyrosine Phosphatase, non-receptor type 11 (PTPN11) are seen in
approximately 5-10% percent of patients with acute myeloid leukemia (AML) that independently confers a poor
prognosis, and is the leukemic driver in 35% of patients with the rare chemoresistant juvenile myelomonocytic
leukemia (JMML). To date, targeting PTPN11 for clinical benefit has not been well established. Our
preliminary data using high-throughput functional assays have identified that PTPN11 activity is dependent on
an upstream tyrosine kinase, TNK2, and that leukemic cells with activating PTPN11 mutants are sensitive to
TNK2 inhibition. The long-term goal of this proposal is to identify novel combinations of targeted
therapies using PTPN11/TNK2 dependent leukemias as a model. The immediate goals are to
comprehensively understand the molecular mechanisms of PTPN11 activation, and to define
therapeutic regimens for treatment based on the central hypothesis that PTPN11-dependent leukemias
are directly activated by TNK2. To accomplish these goals, several key AIMS will need to be addressed: 1)
Develop a detailed understanding of the biochemical pathways interacting with activated PTPN11. We will
use molecular and biochemical studies to dissect the interactions of proteins within PTPN11/TNK2 and
downstream pathways through heterologous model systems, PTPN11 mutant AML cell lines, murine bone
marrow cells with mutant PTPTN11, and primary mutant PTPN11 AML samples. Further, RNAi and
CRISPR technology will be utilized to selectively inhibit expression of candidate proteins to identify
critical interactions necessary for PTPN11/TNK2 activity within hematopoietic model systems. These studies
will establish the molecular and biochemical foundation necessary for defining PTPN11/TNK2 activation, and
help guide novel targeted approaches. 2) Test combination pathway inhibition to overcome escape from
monotherapy. We will use our experience and expertise with small molecule inhibitors to identify synergistic
combinations of inhibitors to TNK2, PTPN11, modulators of PTPN11/TNK2 activation, and downstream
effectors in vitro using cell lines and primary patient samples. Molecular and biochemical studies will be
performed on samples that overcome therapy to identify escape mechanisms. These studies will define the use
of combination therapy for treatment of PTPN11-driven leukemias and provide critical pre-clinical data for
further development of these combinations. 3) Test combination therapies in the animal model. We will test the
above combinations in vivo using mouse models harboring PTPN11 mutations, as well as primary patient
leukemia samples with PTPN11 mutations xenografted into immunodeficient mice. These studies will build the
preclinical foundation for combination of targeted therapies for eventual use in patients with PTPN11-driven
leukemias.
蛋白酪氨酸磷酸酶非受体11(PTPN11)的激活突变可见于
约5%-10%的急性髓系白血病(AML)患者独立诊断为
预后,在35%的罕见耐药青少年粒单核细胞患者中是白血病的驱动因素
白血病(JMML)。到目前为止,针对PTPN11的临床益处还没有得到很好的证实。我们的
使用高通量功能分析的初步数据已经确定PTPN11的活性依赖于
一种上游酪氨酸激酶TNK2,具有激活PTPN11突变体的白血病细胞对其敏感
TNK2抑制作用。这项提议的长期目标是确定有针对性的
以PTPN11/TNK2依赖白血病为模型的治疗。眼前的目标是
全面了解PTPN11激活的分子机制,并确定
基于PTPN11依赖白血病的中心假设的治疗方案
是由TNK2直接激活的。要实现这些目标,需要解决几个关键目标:1)
详细了解与激活的PTPN11相互作用的生化途径。我们会
利用分子和生化研究来剖析PTPN11/TNK2和PTPN11/TNK2中蛋白质之间的相互作用
通过异源模型系统、PTPN11突变型AML细胞系、小鼠骨的下游通路
带有突变PTN11的骨髓细胞和主要突变的PTPN11 AML样本。此外,RNAi和
将利用CRISPR技术选择性抑制候选蛋白的表达以鉴定
造血模型系统中PTPN11/TNK2活性所需的关键相互作用。这些研究
将建立确定PTPN11/TNK2激活所需的分子和生化基础,以及
帮助指导新的有针对性的方法。2)测试组合通路抑制以克服逃避
单一疗法。我们将利用我们在小分子抑制剂方面的经验和专业知识来确定协同作用
TNK2、PTPN11的抑制剂、PTPN11/TNK2激活的调节剂及其下游的组合
使用细胞系和初级患者样本进行体外效应。分子和生化研究将是
对战胜治疗的样本进行测试,以确定逃逸机制。这些研究将确定其用途
联合疗法治疗PTPN11驱动的白血病并提供关键的临床前数据
这些组合的进一步发展。3)在动物模型上测试联合疗法。我们将测试
上述组合在体内使用携带PTPN11突变的小鼠模型以及原发患者
携带PTPN11突变的白血病样本异种移植到免疫缺陷小鼠体内。这些研究将建立
PTPN11驱动的患者最终使用联合靶向治疗的临床前基础
白血病。
项目成果
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{{ truncateString('BILL H CHANG', 18)}}的其他基金
Targeting PTPN11 dependent Hematologic Malignancies
靶向 PTPN11 依赖性血液恶性肿瘤
- 批准号:
10057374 - 财政年份:2019
- 资助金额:
$ 34.52万 - 项目类别:
Targeting PTPN11 dependent Hematologic Malignancies
靶向 PTPN11 依赖性血液恶性肿瘤
- 批准号:
10305637 - 财政年份:2019
- 资助金额:
$ 34.52万 - 项目类别:
Aurora B kinase is the downstream target of ATR
Aurora B 激酶是 ATR 的下游靶点
- 批准号:
6999573 - 财政年份:2005
- 资助金额:
$ 34.52万 - 项目类别: