Investigating DNA repair vulnerabilities in oncometabolite producing cancers
研究产生肿瘤代谢物的癌症中的 DNA 修复漏洞
基本信息
- 批准号:10672173
- 负责人:
- 金额:$ 4.77万
- 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:2021-08-17 至 2024-08-16
- 项目状态:已结题
- 来源:
- 关键词:AffectBiological AssayCancer PatientCell LineCell SurvivalCellsChIP-seqChromatinCitric Acid CycleDNADNA DamageDNA Double Strand BreakDNA RepairDNA Repair PathwayDNA-dependent protein kinaseDataDependenceDevelopmentDisease ProgressionDouble Strand Break RepairEnzymesEquilibriumEventFlow CytometryFrequenciesFumarate HydrataseFumaratesFutureGenesGenomeGliomaImmunofluorescence ImmunologicIsocitrate DehydrogenaseKnowledgeLeadLigandsLigationMalignant NeoplasmsMolecular TargetMonitorMutationNonhomologous DNA End JoiningParagangliomaPathway interactionsPheochromocytomaPoly(ADP-ribose) Polymerase InhibitorPoly(ADP-ribose) PolymerasesProcessProductionProteinsRenal Cell CarcinomaReporterReportingResearchRoleSignal TransductionSiteSuccinate DehydrogenaseSuccinatesTestingTherapeuticUp-Regulationcancer health disparitycancer therapyclinical developmentclinically relevantcytotoxicefficacy evaluationhomologous recombinationinhibitorinsightmutantneoplastic cellnovel therapeutic interventionnovel therapeuticsrecruitrepairedresponsesmall molecule inhibitorsynergismtherapeutic targettherapeutically effectivetranslational approachtreatment strategy
项目摘要
PROJECT SUMMARY
Cancer-associated mutations in tricarboxylic acid cycle genes induce production of 2-hydroxyglutarate ,
fumarate, or succinate. These oncometabolites suppress the homologous recombination (HR) DNA repair
pathway. Nonhomologous end joining (NHEJ) is the other major pathway for double strand break (DSB) repair,
which is further sub-divided into classical (cNHEJ) and highly mutagenic alternative end joining (altNHEJ)
pathways. Our group’s preliminary data suggests that oncometabolites induce upregulation of NHEJ repair,
however, the mechanistic basis for this observation has yet to be elucidated. Multiple inhibitors have been
developed that target proteins within these NHEJ repair pathways, including DNA-PK and pol theta inhibitors,
which suggests that NHEJ is a clinically relevant target. I hypothesize specific oncometabolites uniquely
and dynamically regulate altNHEJ and cNHEJ, which can be targeted for a therapeutic gain against
tumor cells.
I will investigate how oncometabolites alter DSB repair and evaluate NHEJ pathways as therapeutic
targets through two aims. My first aim will elucidate the dynamic balance between NHEJ pathways in
oncometabolite producing cells. I will use U2OS cells that express reporters specific for HR, total NHEJ, and
altNHEJ to determine how oncometabolites, added exogenously or intrinsically produced by mutations, alter
NHEJ frequency. To determine how cNHEJ and altNHEJ protein recruitment is altered at DNA break sites with
diverse chromatin states, I will use both immunofluorescence and chromatin immunoprecipitation sequencing
(ChIP-seq) in a cell line in which endogenous double strand breaks can be induced at hundreds of sites in the
genome. Changes in the timing of protein recruitment will be studied using ChIP-seq for cNHEJ or altNHEJ
proteins identified by immunofluorescence. This will establish the extent to which oncometabolites alter various
stages of NHEJ, such as DNA end processing or ligation. My second aim will investigate the effect of
cNHEJ and altNHEJ inhibition on oncometabolite producing cancers. I will target cNHEJ and altNHEJ
with DNA-PK and pol theta inhibitors, respectively, by performing short-term cell viability assays in
oncometabolite producing cell lines. This will determine whether oncometabolite producing cancers are more
sensitive to DNA-PK or pol theta inhibitors as single agents compared to parental cell lines. Furthermore, these
cell lines show exquisite sensitivity to PARP inhibitors. I will evaluate potential therapeutic combinations by
testing the sensitivity of these cell lines to DNA-PK inhibitors and pol theta inhibitors in combination with PARP
inhibitors. This will determine whether targeting both cNHEJ or altNHEJ and PARP is more effective than
single agents alone. Overall, this proposal will lead to a more complete understanding of how oncometabolites
affect DSB repair and identify novel therapeutic strategies for treatment of oncometabolite producing cancers.
项目概要
癌症相关的三羧酸循环基因突变诱导 2-羟基戊二酸的产生,
这些致癌代谢物抑制同源重组 (HR) DNA 修复。
非同源末端连接(NHEJ)是双链断裂(DSB)修复的另一个主要途径。
进一步细分为经典(cNHEJ)和高诱变选择性末端连接(altNHEJ)
我们小组的初步数据表明,肿瘤代谢物会诱导 NHEJ 修复上调,
然而,这种观察的机制基础尚未阐明。多种抑制剂尚未阐明。
开发了这些 NHEJ 修复途径中的靶蛋白,包括 DNA-PK 和 pol theta 抑制剂,
这表明 NHEJ 是一个临床相关靶点。
并动态调节 altNHEJ 和 cNHEJ,可针对针对
肿瘤细胞。
我将研究肿瘤代谢物如何改变 DSB 修复并评估 NHEJ 通路的治疗作用
我的第一个目标是阐明 NHEJ 通路之间的动态平衡。
我将使用表达 HR、总 NHEJ 和特异性的 U2OS 细胞。
altNHEJ 确定由突变外源添加或内在产生的肿瘤代谢物如何改变
NHEJ 频率以确定 cNHEJ 和 altNHEJ 蛋白募集如何在 DNA 断裂位点发生改变。
不同的染色质状态,我将使用免疫荧光和染色质免疫沉淀测序
(ChIP-seq)在细胞系中,可以在细胞的数百个位点诱导内源双链断裂
将使用 cNHEJ 或 altNHEJ 的 ChIP-seq 研究蛋白质招募时间的变化。
通过免疫荧光鉴定的蛋白质这将确定肿瘤代谢物改变各种变化的程度。
NHEJ 的各个阶段,例如 DNA 末端加工或连接,我的第二个目标是研究其效果。
cNHEJ 和 altNHEJ 对产生肿瘤代谢物的癌症的抑制作用我将针对 cNHEJ 和 altNHEJ。
分别使用 DNA-PK 和 pol theta 抑制剂,通过在
产生致癌代谢物的细胞系这将决定产生致癌代谢物的癌症是否更多。
与亲代细胞系相比,这些细胞系对 DNA-PK 或 pol theta 抑制剂作为单一药物敏感。
细胞系对 PARP 抑制剂表现出极高的敏感性,我将通过以下方式评估潜在的治疗组合。
测试这些细胞系对 DNA-PK 抑制剂和 pol theta 抑制剂与 PARP 组合的敏感性
这将决定同时靶向 cNHEJ 或 altNHEJ 和 PARP 是否比靶向抑制剂更有效。
总体而言,该提案将导致人们更全面地了解肿瘤代谢物的作用。
影响 DSB 修复并确定治疗产生致癌代谢物的癌症的新治疗策略。
项目成果
期刊论文数量(26)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Synthesis-dependent microhomology-mediated end joining accounts for multiple types of repair junctions.
- DOI:10.1093/nar/gkq379
- 发表时间:2010-09
- 期刊:
- 影响因子:14.9
- 作者:Yu AM;McVey M
- 通讯作者:McVey M
Polθ inhibitors elicit BRCA-gene synthetic lethality and target PARP inhibitor resistance.
- DOI:10.1038/s41467-021-23463-8
- 发表时间:2021-06-17
- 期刊:
- 影响因子:16.6
- 作者:Zatreanu D;Robinson HMR;Alkhatib O;Boursier M;Finch H;Geo L;Grande D;Grinkevich V;Heald RA;Langdon S;Majithiya J;McWhirter C;Martin NMB;Moore S;Neves J;Rajendra E;Ranzani M;Schaedler T;Stockley M;Wiggins K;Brough R;Sridhar S;Gulati A;Shao N;Badder LM;Novo D;Knight EG;Marlow R;Haider S;Callen E;Hewitt G;Schimmel J;Prevo R;Alli C;Ferdinand A;Bell C;Blencowe P;Bot C;Calder M;Charles M;Curry J;Ekwuru T;Ewings K;Krajewski W;MacDonald E;McCarron H;Pang L;Pedder C;Rigoreau L;Swarbrick M;Wheatley E;Willis S;Wong AC;Nussenzweig A;Tijsterman M;Tutt A;Boulton SJ;Higgins GS;Pettitt SJ;Smith GCM;Lord CJ
- 通讯作者:Lord CJ
Analysis of drug combinations: current methodological landscape.
- DOI:10.1002/prp2.149
- 发表时间:2015-06
- 期刊:
- 影响因子:2.6
- 作者:Foucquier, Julie;Guedj, Mickael
- 通讯作者:Guedj, Mickael
Transcriptionally active chromatin recruits homologous recombination at DNA double-strand breaks.
- DOI:10.1038/nsmb.2796
- 发表时间:2014-04
- 期刊:
- 影响因子:16.8
- 作者:Aymard F;Bugler B;Schmidt CK;Guillou E;Caron P;Briois S;Iacovoni JS;Daburon V;Miller KM;Jackson SP;Legube G
- 通讯作者:Legube G
Identification of novel radiosensitizers in a high-throughput, cell-based screen for DSB repair inhibitors.
- DOI:10.1158/1535-7163.mct-14-0765
- 发表时间:2015-02
- 期刊:
- 影响因子:5.7
- 作者:Goglia AG;Delsite R;Luz AN;Shahbazian D;Salem AF;Sundaram RK;Chiaravalli J;Hendrikx PJ;Wilshire JA;Jasin M;Kluger HM;Glickman JF;Powell SN;Bindra RS
- 通讯作者:Bindra RS
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Katelyn Noronha其他文献
Katelyn Noronha的其他文献
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{{ truncateString('Katelyn Noronha', 18)}}的其他基金
Investigating DNA repair vulnerabilities in oncometabolite producing cancers
研究产生肿瘤代谢物的癌症中的 DNA 修复漏洞
- 批准号:
10393503 - 财政年份:2021
- 资助金额:
$ 4.77万 - 项目类别:
Investigating DNA repair vulnerabilities in oncometabolite producing cancers
研究产生肿瘤代谢物的癌症中的 DNA 修复漏洞
- 批准号:
10229137 - 财政年份:2021
- 资助金额:
$ 4.77万 - 项目类别:
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