Project 2: Defining and exploiting genetic dependencies in complex karyotype AML
项目 2:定义和利用复杂核型 AML 中的遗传依赖性
基本信息
- 批准号:10474281
- 负责人:
- 金额:$ 36.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-24 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:17pAcute Myelocytic LeukemiaAddressAnimal ModelAntitumor ResponseBiologicalCancer ModelCell LineCessation of lifeChemoresistanceChromatinChromosome abnormalityChromosomesClinicalClinical TrialsCollaborationsComplexCytogenetic AnalysisDataDeletion MutationDependenceDevelopmentDiagnosisDiseaseDisease modelDrug TargetingEnzymesEpigenetic ProcessEventFLT3 geneFaceFrequenciesGene ExpressionGeneticGenetic ModelsGenetic TranscriptionGenetically Engineered MouseGenomeGenomicsGenotypeHumanJAK2 geneKaryotypeKaryotype determination procedureKetoglutarate Dehydrogenase ComplexMalignant NeoplasmsMemorial Sloan-Kettering Cancer CenterMetabolismMethodsModelingMolecularMutationMutation AnalysisOncogenesOncogenicOncoproteinsOutcomePathogenesisPatient-Focused OutcomesPatientsPharmacologyPre-Clinical ModelPrognosisProteinsRecurrenceResearchResearch PersonnelResistanceResolutionResourcesSafetySamplingSolidSpecimenStudy modelsSystemTP53 geneTestingTherapeuticTumor Suppressor GenesTumor Suppressor ProteinsWorkactionable mutationacute myeloid leukemia cellantileukemic activitycandidate validationchemotherapychromosome 5q losscohortcostdiagnostic accuracydigitaleffective therapyexhaustionhuman diseasehuman modelimprovedinhibitorinnovationinsightleukemiamouse modelmutantnew therapeutic targetnext generation sequencingnovelnovel therapeutic interventionnovel therapeuticspatient derived xenograft modelpre-clinicalpreclinical studyprogramsself-renewalsmall molecule inhibitortherapeutic developmenttherapeutic targettherapeutically effectivetooltranscriptometranscriptome sequencingtumortumorigenicwhole genome
项目摘要
ABSTRACT
Complex karyotype acute myeloid leukemia (CK AML) is defined by the presence of 3 or more detectable
cytogenetic abnormalities and has one of the least favorable prognoses of any leukemia genotype. Genomic
characterization indicates that this disease lacks conventional druggable oncoproteins, but instead is
characterized by a set of recurrent segmental deletions and mutations in the TP53 tumor suppressor gene, the
latter of which are absent from normal karyotype AML and confer resistance to standard chemotherapies. To
better characterize the pathogenesis of CK AML and to develop new strategies to treat this disease, we will
exhaustively analyze the genomes of a large cohort of CK AML samples using a new low-cost, high-resolution
platform optimized in our group called “digital karyotyping”. These molecular features will be correlated with
patient outcomes data, and used to generate murine and human models that accurately recapitulate CK AML-
specific features. We will use these models to test a new therapeutic strategy for countering the pro-tumorigenic
effects of p53 loss. This concept builds on preliminary data showing that p53 loss can perturb cellular metabolism
in a manner that alters gene expression and drives aberrant self-renewal, and that reversing these effects with
small molecule inhibitors can drive differentiation of p53-deficient AML. Specifically, we have found that p53
mutations reduce levels of the metabolite aKG, producing similar effects of oncogenic IDH1/2 mutant proteins
that have proven to be drug targets in other sub-types of AML. In models studied to date, the tumor suppressive
effects of p53 are recapitulated by inhibiting the TCA enzyme 2-oxoglutarate dehydrogenase (OGDH) and, as
such, we consider OGDH a prime candidate for validation and development in CK AML. Successful completion
of the proposed research will produce a detailed understanding of the genetic changes that accompany CK AML
and allow for more faithful modeling of human disease. In addition, we hypothesize that oxoglutarate
dehydrogenase (OGDH) a promising therapeutic target for the treatment of CK AML. Validating our novel drug
target will pave the way for clinical trials in this indication. Given the paucity of effective therapeutic options for
patients with CK AML, the proposed studies address an urgent, unmet clinical need.
摘要
复杂核型急性髓细胞白血病(CK AML)是指存在3个或更多可检测的
细胞遗传学异常,并且具有任何白血病基因型中最不利的遗传学特征之一。基因组
表征表明,这种疾病缺乏常规的可药物化的癌蛋白,而是
其特征在于TP 53肿瘤抑制基因中的一组复发性节段性缺失和突变,
后者在正常核型AML中不存在,并赋予对标准化疗的抗性。到
为了更好地描述CK AML的发病机制并开发治疗这种疾病的新策略,我们将
使用新的低成本,高分辨率,
在我们的小组中优化的平台称为“数字核型分析”。这些分子特征将与
患者结果数据,并用于生成准确概括CK AML的鼠和人模型-
具体特点。我们将使用这些模型来测试一种新的治疗策略,
p53缺失的影响这一概念建立在初步数据的基础上,这些数据表明p53的缺失会扰乱细胞代谢。
以改变基因表达和驱动异常自我更新的方式,
小分子抑制剂可以驱动p53缺陷型AML的分化。我们发现,p53
突变降低代谢物aKG的水平,产生与致癌IDH 1/2突变蛋白相似的作用
已经被证明是其他AML亚型的药物靶点。在迄今为止研究的模型中,
p53的作用通过抑制TCA酶2-酮戊二酸脱氢酶(OGDH)而重现,
因此,我们认为OGDH是在CK AML中验证和开发主要候选者。成功完成
这项拟议中的研究将详细了解伴随CK AML的遗传变化,
并允许对人类疾病进行更忠实的建模。此外,我们假设酮戊二酸
脱氢酶(OGDH)是治疗CK AML的有希望的治疗靶点。验证我们的新药
Target将为该适应症的临床试验铺平道路。由于缺乏有效的治疗选择,
对于CK AML患者,拟定的研究解决了一个紧迫的、未满足的临床需求。
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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SCOTT W. LOWE其他文献
SCOTT W. LOWE的其他文献
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{{ truncateString('SCOTT W. LOWE', 18)}}的其他基金
Mechanisms of p53 Engagement and Action at the Benign-to-Malignant Transition in Sporadic Tumorigenesis
p53在散发性肿瘤发生良性向恶性转变中的参与和作用机制
- 批准号:
10720034 - 财政年份:2023
- 资助金额:
$ 36.77万 - 项目类别:
Systematic characterization of cancer variants using single-cell functional genomics
使用单细胞功能基因组学对癌症变异进行系统表征
- 批准号:
10599180 - 财政年份:2022
- 资助金额:
$ 36.77万 - 项目类别:
Systematic characterization of cancer variants using single-cell functional genomics
使用单细胞功能基因组学对癌症变异进行系统表征
- 批准号:
10358184 - 财政年份:2022
- 资助金额:
$ 36.77万 - 项目类别:
Impact of the aging niche on cancer phenotypes probed using mouse cancer models produced by somatic engineering.
使用体细胞工程产生的小鼠癌症模型探讨衰老生态位对癌症表型的影响。
- 批准号:
10355559 - 财政年份:2021
- 资助金额:
$ 36.77万 - 项目类别:
Rapid and flexible precision oncology mouse models of epithelial malignancies epithelial malignancies
快速灵活的上皮恶性肿瘤精准肿瘤学小鼠模型
- 批准号:
10318154 - 财政年份:2020
- 资助金额:
$ 36.77万 - 项目类别:
Toward development of senolytic CAR T cells
致力于开发 senolytic CAR T 细胞
- 批准号:
10599858 - 财政年份:2020
- 资助金额:
$ 36.77万 - 项目类别:
Toward development of senolytic CAR T cells
致力于开发 senolytic CAR T 细胞
- 批准号:
10161683 - 财政年份:2020
- 资助金额:
$ 36.77万 - 项目类别:
Rapid and flexible precision oncology mouse models of epithelial malignancies epithelial malignancies
快速灵活的上皮恶性肿瘤精准肿瘤学小鼠模型
- 批准号:
9886845 - 财政年份:2020
- 资助金额:
$ 36.77万 - 项目类别:
Rapid and flexible precision oncology mouse models of epithelial malignancies epithelial malignancies
快速灵活的上皮恶性肿瘤精准肿瘤学小鼠模型
- 批准号:
10545181 - 财政年份:2020
- 资助金额:
$ 36.77万 - 项目类别:
Toward development of senolytic CAR T cells
致力于开发 senolytic CAR T 细胞
- 批准号:
10374901 - 财政年份:2020
- 资助金额:
$ 36.77万 - 项目类别:
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