Averting recurrent and resistant ovarian tumors
避免复发性和耐药性卵巢肿瘤
基本信息
- 批准号:10058817
- 负责人:
- 金额:$ 49.08万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-19 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:BackBypassCancer EtiologyCancer PatientCancer RelapseCancer SurvivorCessation of lifeChemoresistanceCisplatinDNA DamageDNA biosynthesisDNA-Directed DNA PolymeraseDevelopmentDown-RegulationDrug resistanceEpithelial ovarian cancerGenomic InstabilityGoalsIn complete remissionInduced MutationLongevityMalignant Female Reproductive System NeoplasmMalignant NeoplasmsMalignant neoplasm of ovaryMediatingMutagenesisMutationNatural regenerationOperative Surgical ProceduresOvarianPatient-Focused OutcomesPharmaceutical PreparationsPlasmidsPlatinumPolymeraseRecurrenceRecurrent tumorRefractoryRegimenRelapseResistanceRoleSchemeSigns and SymptomsSolidStem Cell DevelopmentTestingTetanus Helper PeptideTreatment FailureTumorigenicityUnited StatesWomanXenograft Modelanticancer researchbasecancer cellcancer cell differentiationcancer stem cellcancer survivalchemotherapycrosslinkexpectationimproved outcomemortalityneoplastic cellnovelnovel therapeuticsovarian neoplasmpreventsmall hairpin RNAstem cell survivaltumortumor xenografttumorigenic
项目摘要
Tumor relapse and acquired chemotherapy resistance are two major factors leading to the high mortality of
epithelial ovarian cancer (EOC) patients. It has become increasingly evident that ovarian cancers contain
subpopulations of cancer stem cells (CSCs) with enhanced tumorigenicity and chemoresistance. These CSCs
are believed to be responsible for treatment failure and tumor relapse. However, it is still unclear how CSCs
survive DNA-damaging agent treatment, and how the tumor regenerated by the surviving CSCs develops
chemoresistance. Error-prone translesion DNA synthesis (TLS), a DNA damage tolerance mechanism that
bypasses DNA damage during replication, has been suggested to mediate acquired chemoresistance. Our
recent studies have revealed that ovarian CSCs show elevated expression of TLS polymerase η (Polη); we
also demonstrated that Polη is critical to the survival of ovarian CSCs following cisplatin treatment. Based on
this scientific premise, we generate a hypothesis that enhanced Polη-mediated TLS in CSCs contributes to
tumor relapse and the development of acquired cisplatin-resistance after initial cisplatin treatment, by
facilitating CSC survival and increasing CSC mutagenesis. The main objective of this proposal is to determine
a novel mechanism that contributes to EOC relapse and chemotherapeutic resistance following initial cisplatin
treatment. Two specific aims are proposed to test this hypothesis and achieve our goal. In specific aim 1, we
will determine the contribution of Polη-mediated TLS to EOC relapse after cisplatin treatment. In specific aim 2,
we will delineate the contribution of Polη-mediated TLS to the development of acquired cisplatin resistance in
the EOC and cisplatin-induced mutations in ovarian CSCs. The rationale under this proposal is that
understanding the mechanism underlying tumor relapse and chemotherapy resistance would facilitate the
development of new therapy strategies to improve the outcome of patients with EOC. It is our expectation that
at the conclusion of this project, we will have provided solid evidence showing that enhanced expression of
Polη in ovarian CSCs contributes to the tumor regrowth, mutagenesis in CSCs, and the development of
cisplatin resistance after initial cisplatin treatment. Downregulation of Polη would significantly inhibit tumor
relapse and prevent the development of cisplatin resistance, and thus, can be exploited for a new therapy
strategy for EOCs.
肿瘤复发和获得性化疗耐药是导致恶性肿瘤高死亡率的两个主要因素,
上皮性卵巢癌(EOC)患者。越来越明显的是,卵巢癌含有
肿瘤干细胞(CSCs)的亚群具有增强的致瘤性和化学抗性。这些CSC
被认为是治疗失败和肿瘤复发的原因。然而,目前尚不清楚CSCs如何
存活的DNA损伤剂治疗,以及存活的CSC再生的肿瘤如何发展
化学抗性易错跨损伤DNA合成(TLS),一种DNA损伤耐受机制,
在复制过程中绕过DNA损伤,已被认为介导获得性化学抗性。我们
最近的研究表明,卵巢CSC显示TLS聚合酶η(Polη)的表达升高;我们
也证明Polη对顺铂治疗后卵巢CSC的存活至关重要。基于
在这个科学前提下,我们提出了一个假设,即CSC中增强的Polη介导的TLS有助于
在初始顺铂治疗后肿瘤复发和获得性顺铂耐药性的发展,
促进CSC存活和增加CSC诱变。本提案的主要目的是确定
一种导致EOC复发和初始顺铂化疗耐药的新机制
治疗提出了两个具体的目标来检验这一假设,实现我们的目标。在具体目标1中,我们
将确定Polη介导的TLS对顺铂治疗后EOC复发的贡献。在具体目标2中,
我们将描述Polη介导的TLS对获得性顺铂耐药的作用,
EOC和顺铂诱导的卵巢CSC突变。这项建议的理由是,
了解肿瘤复发和化疗耐药的机制将有助于
开发新的治疗策略以改善EOC患者的结局。我们期望
在这个项目结束时,我们将提供确凿的证据表明,增强表达的
卵巢CSCs中的Polη有助于肿瘤的再生长、CSCs中的诱变以及肿瘤的发生。
初始顺铂治疗后的顺铂耐药性。下调Polη的表达可显著抑制肿瘤的生长
复发和预防顺铂耐药性的发展,因此,可以开发新的治疗方法
EOC战略。
项目成果
期刊论文数量(6)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Depleting ovarian cancer stem cells with calcitriol.
- DOI:10.18632/oncotarget.24520
- 发表时间:2018-03-06
- 期刊:
- 影响因子:0
- 作者:Srivastava AK;Rizvi A;Cui T;Han C;Banerjee A;Naseem I;Zheng Y;Wani AA;Wang QE
- 通讯作者:Wang QE
Core signaling pathways in ovarian cancer stem cell revealed by integrative analysis of multi-marker genomics data.
- DOI:10.1371/journal.pone.0196351
- 发表时间:2018
- 期刊:
- 影响因子:3.7
- 作者:Zhang T;Xu J;Deng S;Zhou F;Li J;Zhang L;Li L;Wang QE;Li F
- 通讯作者:Li F
DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1.
- DOI:10.1038/s41419-018-0585-y
- 发表时间:2018-05-01
- 期刊:
- 影响因子:9
- 作者:Cui T;Srivastava AK;Han C;Wu D;Wani N;Liu L;Gao Z;Qu M;Zou N;Zhang X;Yi P;Yu J;Bell EH;Yang SM;Maloney DJ;Zheng Y;Wani AA;Wang QE
- 通讯作者:Wang QE
EPB41L3 is a potential tumor suppressor gene and prognostic indicator in esophageal squamous cell carcinoma.
- DOI:10.3892/ijo.2018.4316
- 发表时间:2018-05
- 期刊:
- 影响因子:5.2
- 作者:Zeng R;Liu Y;Jiang ZJ;Huang JP;Wang Y;Li XF;Xiong WB;Wu XC;Zhang JR;Wang QE;Zheng YF
- 通讯作者:Zheng YF
NADH protect against radiation enteritis by enhancing autophagy and inhibiting inflammation through PI3K/AKT pathway.
- DOI:
- 发表时间:2018
- 期刊:
- 影响因子:2.2
- 作者:Jinting Wang;Wenxi Xie;Faquan Liu;Y. Bi;Xiongjie Zhu;Qi-En Wang;Yan-Fang Zheng
- 通讯作者:Jinting Wang;Wenxi Xie;Faquan Liu;Y. Bi;Xiongjie Zhu;Qi-En Wang;Yan-Fang Zheng
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{{ truncateString('Qien Wang', 18)}}的其他基金
Role of ALDH in PARP inhibitor resistance in HR-deficient ovarian cancer
ALDH 在 HR 缺陷卵巢癌 PARP 抑制剂耐药中的作用
- 批准号:
10394792 - 财政年份:2021
- 资助金额:
$ 49.08万 - 项目类别:
Role of ALDH in PARP inhibitor resistance in HR-deficient ovarian cancer
ALDH 在 HR 缺陷卵巢癌 PARP 抑制剂耐药中的作用
- 批准号:
10606619 - 财政年份:2021
- 资助金额:
$ 49.08万 - 项目类别:
Role of DDB2 in chemotherapeutic agents-induced apoptosis and platinum resistance
DDB2 在化疗药物诱导的细胞凋亡和铂类耐药中的作用
- 批准号:
8323286 - 财政年份:2011
- 资助金额:
$ 49.08万 - 项目类别:
Role of DDB2 in chemotherapeutic agents-induced apoptosis and platinum resistance
DDB2 在化疗药物诱导的细胞凋亡和铂类耐药中的作用
- 批准号:
8711333 - 财政年份:2011
- 资助金额:
$ 49.08万 - 项目类别:
Role of DDB2 in chemotherapeutic agents-induced apoptosis and platinum resistance
DDB2 在化疗药物诱导的细胞凋亡和铂类耐药中的作用
- 批准号:
8516879 - 财政年份:2011
- 资助金额:
$ 49.08万 - 项目类别:
Role of DDB2 in chemotherapeutic agents-induced apoptosis and platinum resistance
DDB2 在化疗药物诱导的细胞凋亡和铂类耐药中的作用
- 批准号:
8050717 - 财政年份:2011
- 资助金额:
$ 49.08万 - 项目类别:
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