Therapeutic targeting of SIRT3 for aggressive and refractory lymphomas
SIRT3 治疗侵袭性和难治性淋巴瘤的靶向治疗
基本信息
- 批准号:10587454
- 负责人:
- 金额:$ 67.99万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-03-02 至 2028-02-29
- 项目状态:未结题
- 来源:
- 关键词:Acetyl Coenzyme AAmino AcidsApoptosisAutophagocytosisB-LymphocytesBasic ScienceBiochemicalBiochemical PathwayBiologicalBiological AssayBiological ModelsBiologyBypassCellsChemoresistanceCitric Acid CycleClinicClinicalComplexDataDeacetylaseDeacetylationEnzymesGenerationsGeneticGenetic HeterogeneityGlutamineGrowthImpairmentIn VitroInferiorInterventionKnockout MiceLeadLinkLymphomaLymphoma cellLymphomagenesisLysineMediatorMetabolicMetabolic PathwayMetabolismMitochondriaMusMutationNutrientOutcomeOxidoreductasePathway interactionsPatientsPharmaceutical PreparationsPhysiologicalPrecision therapeuticsProductionProliferatingRecurrenceRefractoryRegimenReportingResearchResistanceRoleSirtuinsSomatic MutationStressStructure of germinal center of lymph nodeTextTherapeuticTranslatingTreatment EfficacyTumor Suppressor ProteinsWorkcell killingchemotherapyclinical translationcombinatorialeffective therapyimprovedin vivoinhibitorknock-downlarge cell Diffuse non-Hodgkin&aposs lymphomaloss of functionmolecular targeted therapiesnoveloverexpressionpatient subsetspharmacologicprecision medicinepreventprogramsrational designresistance mechanismsmall moleculesmall molecule inhibitortargeted agenttargeted treatmenttherapeutic targettumor
项目摘要
ABSTRACT
Among aggressive lymphomas, the Diffuse large B-cell lymphomas (DLBCLs) are among the
most highly proliferative, and have massive requirements for production of metabolic precursors.
Along these lines we recently identified NAD+ dependent lysine deacetylase SIRT3, as a master
regulator of mitochondrial stress metabolism, as a critical driver of DLBCL growth and
survival. We showed that SIRT3 loss of function in DLBCL cells kills lymphomas by disrupting
their ability to use glutamine and other amino acids in the TCA cycle, which triggers destructive
autophagy – both in vitro and in vivo. Importantly, we created the mitochondrial targeted SIRT3
selective small molecule YC8-02 that precisely mimics the effect of SIRT3 depletion and potently
killed DLBCL cells in vitro and in vivo. These compounds yielded further enhanced killing effects
in combination with targeted therapies such as venetoclax as well with chemotherapy drugs
commonly used to treat DLBCLs. Finally, our mechanistic data point to pathways in cells that
could eventually lead to resistance to SIRT3 targeted therapy, as well as ways to prevent this
from happening so as to yield maximal therapeutic efficacy. An overarching challenge in
delivering precision medicine for DLBCL patients is their marked genetic heterogeneity and
extreme abundance of somatic mutations. There are currently no targeted agents with activity
and targets relevant to more than a small fraction of patients. However, we identified SIRT3
as a broadly relevant and critical non-oncogene addiction that is required by DLBCLs
independent of their genetic background. Through this proposal we provide the basis for i)
translating SIRT3 inhibitors to the clinic, ii) understanding and mitigating potential resistance
mechanisms, and iii) incorporating SIRT3 inhibitors into rationally designed anti-lymphoma
regimens with broad relevance for the subsets of patients who desperately need improved
therapies. Our proposal uses state of the art model systems physiologically relevant to these
complex tumors, and is poised to deliver highly impactful outcomes from the scientific and clinical
perspective.
摘要
在侵袭性淋巴瘤中,弥漫性大B细胞淋巴瘤(DLBCL)是其中之一。
增殖性最高,并且对代谢前体的产生具有大量需求。
沿着这些路线,我们最近确定了NAD+依赖性赖氨酸脱乙酰酶SIRT 3,作为一个主酶,
线粒体应激代谢的调节剂,作为DLBCL生长的关键驱动因素,
生存我们发现DLBCL细胞中SIRT 3功能的丧失通过破坏淋巴瘤细胞的增殖而杀死淋巴瘤。
它们在TCA循环中使用谷氨酰胺和其他氨基酸的能力,
自噬-在体外和体内。重要的是,我们创造了线粒体靶向SIRT 3
选择性小分子YC 8 -02,精确模拟SIRT 3耗竭的作用,
在体外和体内杀死DLBCL细胞。这些化合物产生了进一步增强的杀伤作用
与靶向治疗如维奈托克以及化疗药物联合
常用于治疗DLBCL。最后,我们的机制数据指出,
最终可能导致对SIRT 3靶向治疗的耐药性,以及预防这种耐药性的方法。
以产生最大的治疗效果。一个首要的挑战,
为DLBCL患者提供精准药物是他们显著的遗传异质性,
大量的体细胞突变目前没有有活动的目标代理
和与一小部分患者相关的靶点。然而,我们发现SIRT 3
作为DLBCL所需的广泛相关和关键的非癌基因成瘾
独立于他们的基因背景。通过这一建议,我们为i)
将SIRT 3抑制剂转化为临床,ii)了解和减轻潜在的耐药性
iii)将SIRT 3抑制剂掺入合理设计的抗淋巴瘤药物中,
对于迫切需要改善的患者亚群具有广泛相关性的方案
治疗我们的建议使用与这些生理学相关的最先进的模型系统
复杂的肿瘤,并准备提供高度影响力的结果,从科学和临床
perspective.
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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ARI M. MELNICK其他文献
ARI M. MELNICK的其他文献
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{{ truncateString('ARI M. MELNICK', 18)}}的其他基金
Project 2: The cohesin complex as a tumor suppressor in myeloid leukemia
项目 2:粘连蛋白复合物作为骨髓性白血病的肿瘤抑制因子
- 批准号:
10402272 - 财政年份:2019
- 资助金额:
$ 67.99万 - 项目类别:
Project 2: The cohesin complex as a tumor suppressor in myeloid leukemia
项目 2:粘连蛋白复合物作为骨髓性白血病的肿瘤抑制因子
- 批准号:
10652281 - 财政年份:2019
- 资助金额:
$ 67.99万 - 项目类别:
Project 2: The cohesin complex as a tumor suppressor in myeloid leukemia
项目 2:粘连蛋白复合物作为骨髓性白血病的肿瘤抑制因子
- 批准号:
10153722 - 财政年份:2019
- 资助金额:
$ 67.99万 - 项目类别:
Targeting Epigenetic Circuits in B-Cell Lymphomas
靶向 B 细胞淋巴瘤的表观遗传回路
- 批准号:
10472575 - 财政年份:2018
- 资助金额:
$ 67.99万 - 项目类别:
Targeting Epigenetic Circuits in B-Cell Lymphomas
靶向 B 细胞淋巴瘤的表观遗传回路
- 批准号:
10250403 - 财政年份:2018
- 资助金额:
$ 67.99万 - 项目类别:
Targeting Epigenetic Circuits in B-Cell Lymphomas
靶向 B 细胞淋巴瘤的表观遗传回路
- 批准号:
10689293 - 财政年份:2018
- 资助金额:
$ 67.99万 - 项目类别:
Targeting EZH2 in Germinal Center Derived B-Cell Lymphoma
靶向 EZH2 治疗生发中心衍生的 B 细胞淋巴瘤
- 批准号:
8748763 - 财政年份:2014
- 资助金额:
$ 67.99万 - 项目类别:
Targeting EZH2 in Germinal Center Derived B-Cell Lymphoma
靶向 EZH2 治疗生发中心衍生的 B 细胞淋巴瘤
- 批准号:
9118893 - 财政年份:2014
- 资助金额:
$ 67.99万 - 项目类别:
Targeting EZH2 in Germinal Center Derived B-Cell Lymphoma
靶向 EZH2 治疗生发中心衍生的 B 细胞淋巴瘤
- 批准号:
8906833 - 财政年份:2014
- 资助金额:
$ 67.99万 - 项目类别:
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