Exploring a new therapeutic approach through targeting epigenetic enzymes in ALL
通过针对 ALL 的表观遗传酶探索新的治疗方法
基本信息
- 批准号:9319231
- 负责人:
- 金额:$ 24.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2015
- 资助国家:美国
- 起止时间:2015-09-30 至 2018-08-31
- 项目状态:已结题
- 来源:
- 关键词:Acute Lymphocytic LeukemiaAcute T Cell LeukemiaAdult Acute Lymphocytic LeukemiaAdverse effectsAnimalsApoptosisArchitectureAreaAwardBindingBinding SitesBiochemicalBioinformaticsBone Marrow TransplantationCellsCentral Nervous System ProphylaxisChemicalsChildChildhoodChildhood Hematopoietic NeoplasmChildhood LeukemiaChromatinChromatin ModelingCollaborationsComplexCoupledCranial IrradiationDataData AnalysesDeath RateDefectDiagnosisDisciplineDiseaseDisease ProgressionDisease remissionDrug TargetingDrug usageEducationEndocrine Gland NeoplasmsEnhancersEnvironmentEnzymesEpigenetic ProcessFamilyFluorescent in Situ HybridizationFumaratesFutureGene ExpressionGene FamilyGenesGeneticGenetic Models for CancerGenetic TranscriptionGoalsGrantGrowthHistonesHumanIntrathecal ChemotherapyKnowledgeLinkLysineMaintenanceMalignant NeoplasmsMapsMass Spectrum AnalysisMediastinal MassMediatingMediator of activation proteinMedical centerMentorsMetabolicMetabolic PathwayMetabolismMethylationModelingMolecularMonitorMusMutationMyeloid LeukemiaNOTCH1 geneNeuraxisNew YorkNormal CellNuclearOncogene ActivationOncogenesOncogenicOutcomeOxidative PhosphorylationPathway interactionsPatientsPeripheralPharmaceutical PreparationsPharmacologyPhasePhenotypePhysiologicalPlayPolycombPrincipal InvestigatorProcessProteinsRecruitment ActivityRecurrenceRecurrent diseaseRegulator GenesRelapseResearchRespiratory distressRiskRoleSamplingSuccinate DehydrogenaseSuccinatesT-Cell LeukemiaTechnical ExpertiseTechniquesTestingTherapeuticTimeTissuesToxic effectTrainingTumor InitiatorsTumor Suppressor ProteinsUniversitiesWhite Blood Cell Count procedureWritingbasecancer typecareerchemotherapychromosome conformation captureclinically relevantdesignepigenetic drugexperiencegastrointestinalhigh riskhuman diseaseimprovedin vitro Modelin vivoin vivo Modelinhibitor/antagonistinnovationirradiationkillingsleukemialeukemogenesismalignant statemeetingsmembermouse modelnew therapeutic targetnotch proteinnovel therapeutic interventionoutcome forecastpredictive modelingprognosticprogramspromoterpublic health relevancerelapse patientsresponsible research conductskillssmall molecule inhibitorsymposiumtargeted treatmenttooltranscription factortumor metabolism
项目摘要
DESCRIPTION (provided by applicant): The proposed training grant will facilitate the improvement of the education and career goals of the principal investigator (PI) as well as will lead to important findings in the field of cancer epigenetics with the aim to increase the therapeutic potential in T cell leukemia. Up to 25% of children with acute lymphoblastic leukemia (ALL) will fail frontline therapy and their prognosis is dismal with only 20% cure rate. Although prognosis is better for patients with later relapses, the majority eventually succumbs to the disease (overall cure rate 40 to 50%). Usually, central nervous system (CNS) involvement, lower remission and re-induction rates and early second relapse for those who enter remission are important obstacles in the way to treatment whereas more aggressive types of therapy, including bone marrow transplantation, reached tolerability limits with toxic death rates generally
ranging from 3-19%. Also direct inhibition of Notch pathway in T cell ALL (T-ALL) has been plagued by gastrointestinal toxicity. The hypothesis of this proposal is that epigenetic drugs can be used as a targeted therapy against acute lymphoblastic leukemia, especially when classic chemotherapy and/or irradiation have failed. Using mouse models and primary human samples, we recently identified inactivating genetic alterations of members of the polycomb repressive complex 2 (PRC2) in T-ALL and revealed the importance of the levels of the repressive mark trimethylation of histone 3 lysine 27 (H3K27me3) in leukemogenesis. We have also generated strong data on the prominent but contrasting roles of two H3K27me3 demethylases JUMONJI D3 (JMJD3 or KDM6B) and UTX (or KDM6A) in the same disease. JMJD3 is a facilitator of the oncogenic process whereas UTX is a tumor suppressor although they execute the same enzymatic action. Using a specific chemical inhibitor we were able to kill T cell leukemia, sparing
myeloid leukemia and physiological cells. Moreover we have identified that the family of metabolic genes succinate dehydrogenase (SDH) is transcriptional target of UTX. As these genes have been shown to play tumor suppressor roles in tumors of endocrine origin, we hypothesize, based on strong preliminary results, that a part of UTX action is filtered through SDH family. In the K99 phase of this proposal we aim to: 1) Identify and characterize the oncogenic topological domains (TD) containing NOTCH1 and JMJD3 in leukemia, 2) associate specific TD with disease progression (prognostic model), 3) identify interacting partners for UTX, 4) understand the molecular and physiological roles of SDH in T cell leukemia and 5) to generate and perform basic phenotypic analysis of two animals (mice) modeling mutations of UTX in human disease. During the execution of the K99 phase of this project, the PI will acquire technical skills on chromosome conformation capture techniques, fluorescent In situ hybridization (FISH) and basic metabolic analysis and he will also improve his knowledge on basic bioinformatics (high-throughput data) analysis. In the R00 phase, the candidate will use the skills and tools produced during the K99 phase, use the GSKJ4 inhibitor against demethylases in samples from diagnosis/relapse disease and associate changes with expression and phenotypic changes in the sample as a proof-of-principle for the model interactions. Moreover the PI will fully analyze the tumor suppressor role of UTX through genetic, metabolic, biochemical and epigenetic studies of the generated mouse models. In summary we will set up chromatin models for testing of current drugs and explore metabolic pathways with the perspective to understand the connection between metabolism and epigenetics in cancer and discover new therapeutic targets in the future. We believe that these findings can be applied to other types of cancer, as the mechanisms we explore are universal. The PI has brought together an extensive panel of experienced collaborators and his mentor. This plan includes also regular meetings with members of his advisory board, courses on bioinformatics, networking, grant writing and responsible conduct of research as well as conferences on the aforementioned disciplines (tumor metabolism, genetic models of cancer) so he conveys his ideas and set up collaborations. Overall, the K99 award together with the mentor's and collaborator's experience and the advanced environment of Langone Medical Center at New York University will provide the PI with innovative tools to continue his independent career on the crosstalk between epigenetics and metabolism in leukemia.
描述(由申请人提供):拟议的培训补助金将促进主要研究者(PI)的教育和职业目标的改善,并将导致癌症表观遗传学领域的重要发现,旨在提高T细胞白血病的治疗潜力。高达25%的急性淋巴细胞白血病(ALL)儿童一线治疗失败,其预后很差,治愈率仅为20%。虽然晚期复发的患者预后较好,但大多数最终死于疾病(总治愈率为40 - 50%)。通常,中枢神经系统(CNS)受累、较低的缓解率和再诱导率以及进入缓解期的患者的早期第二次复发是治疗的重要障碍,而更积极的治疗类型(包括骨髓移植)通常达到耐受极限,毒性死亡率较高
范围为3- 19%。此外,直接抑制T细胞ALL(T-ALL)中的Notch途径一直受到胃肠道毒性的困扰。这一建议的假设是,表观遗传药物可以作为一种针对急性淋巴细胞白血病的靶向治疗,特别是当经典的化疗和/或放疗失败。使用小鼠模型和原代人类样本,我们最近确定了T-ALL中多梳抑制复合物2(PRC 2)成员的失活遗传改变,并揭示了组蛋白3赖氨酸27(H3 K27 me 3)的抑制标记三甲基化水平在白血病发生中的重要性。我们还生成了关于两种H3 K27 me 3去甲基化酶JUMONJI D3(JMJD 3或KDM 6 B)和UTX(或KDM 6A)在同一疾病中的突出但相反的作用的强有力的数据。JMJD 3是致癌过程的促进剂,而UTX是肿瘤抑制剂,尽管它们执行相同的酶促作用。使用特定的化学抑制剂,我们能够杀死T细胞白血病,
骨髓性白血病和生理细胞。此外,我们已经确定代谢基因琥珀酸脱氢酶(SDH)家族是UTX的转录靶点。由于这些基因已被证明在内分泌起源的肿瘤中发挥肿瘤抑制作用,因此我们假设,基于强有力的初步结果,UTX作用的一部分通过SDH家族过滤。在本提案的K99阶段,我们的目标是:1)鉴定和表征白血病中含有NOTCH 1和JMJD 3的致癌拓扑结构域(TD),2)将特异性TD与疾病进展相关联(预后模型),3)鉴定UTX的相互作用伴侣,4)了解SDH在T细胞白血病中的分子和生理作用,5)生成并执行两种动物(小鼠)的基本表型分析在人类疾病中建模UTX突变。在本项目K99阶段的执行过程中,PI将获得染色体构象捕获技术、荧光原位杂交(FISH)和基础代谢分析方面的技术技能,并将提高其在基础生物信息学(高通量数据)分析方面的知识。在R 00阶段,候选人将使用K99阶段产生的技能和工具,使用GSKJ 4抑制剂对抗来自诊断/复发疾病的样本中的脱甲基酶,并将变化与样本中的表达和表型变化相关联,作为模型相互作用的原理证明。此外,PI将通过对生成的小鼠模型进行遗传、代谢、生化和表观遗传研究,全面分析UTX的肿瘤抑制作用。综上所述,我们将建立染色质模型用于测试当前的药物,并探索代谢途径,以了解癌症代谢和表观遗传学之间的联系,并在未来发现新的治疗靶点。我们相信这些发现可以应用于其他类型的癌症,因为我们探索的机制是普遍的。PI汇集了一个由经验丰富的合作者和他的导师组成的广泛小组。该计划还包括与他的顾问委员会成员定期会议,生物信息学课程,网络,赠款写作和负责任的研究行为以及上述学科的会议(肿瘤代谢,癌症的遗传模型),以便他传达他的想法并建立合作。总的来说,K99奖加上导师和合作者的经验以及纽约大学Langone医学中心的先进环境将为PI提供创新工具,以继续他在白血病表观遗传学和代谢之间的串扰方面的独立职业生涯。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
iAMPlified gene expression offers new insights in B cell precursor leukemia subtype.
iAMPlified 基因表达为 B 细胞前体白血病亚型提供了新的见解。
- DOI:10.1080/10428194.2019.1695055
- 发表时间:2020
- 期刊:
- 影响因子:2.6
- 作者:Ntziachristos,Panagiotis
- 通讯作者:Ntziachristos,Panagiotis
A positive feedback loop regulation between NOTCH1 and USP11 in T-cell leukemia.
- DOI:10.1038/s41375-023-02096-4
- 发表时间:2024-01
- 期刊:
- 影响因子:11.4
- 作者:Fijalkowski, Igor;Wang, Jin;Jin, Qi;Van Laere, Jolien;Serafin, Valentina;Crispino, John D.;Ntziachristos, Panagiotis
- 通讯作者:Ntziachristos, Panagiotis
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Panagiotis Ntziachristos其他文献
Panagiotis Ntziachristos的其他文献
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{{ truncateString('Panagiotis Ntziachristos', 18)}}的其他基金
Therapeutic targeting of demethylation-deubiquitination axis in acute leukemia
急性白血病去甲基化-去泛素化轴的治疗靶向
- 批准号:
10133024 - 财政年份:2020
- 资助金额:
$ 24.9万 - 项目类别:
Exploring a new therapeutic approach through targeting epigenetic enzymes in ALL
通过针对 ALL 的表观遗传酶探索新的治疗方法
- 批准号:
9150647 - 财政年份:2015
- 资助金额:
$ 24.9万 - 项目类别:
Exploring a new therapeutic approach through targeting epigenetic enzymes in ALL
通过针对 ALL 的表观遗传酶探索新的治疗方法
- 批准号:
8766030 - 财政年份:2014
- 资助金额:
$ 24.9万 - 项目类别:
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