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
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:
10545181 - 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:
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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