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：
Qien Wang
金额：
$ 49.08万
依托单位：
OHIO STATE UNIVERSITY
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：
https://reporter.nih.gov/project-details/10058817
关键词：
Back Bypass Cancer Etiology Cancer Patient Cancer Relapse Cancer Survivor Cessation of life Chemoresistance Cisplatin DNA Damage DNA biosynthesis DNA-Directed DNA Polymerase Development Down-Regulation Drug resistance Epithelial ovarian cancer Genomic Instability Goals In complete remission Induced Mutation Longevity Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Mediating Mutagenesis Mutation Natural regeneration Operative Surgical Procedures Ovarian Patient-Focused Outcomes Pharmaceutical Preparations Plasmids Platinum Polymerase Recurrence Recurrent tumor Refractory Regimen Relapse Resistance Role Scheme Signs and Symptoms Solid Stem Cell Development Testing Tetanus Helper Peptide Treatment Failure Tumorigenicity United States Woman Xenograft Model anticancer research base cancer cell cancer cell differentiation cancer stem cell cancer survival chemotherapy crosslink expectation improved outcome mortality neoplastic cell novel novel therapeutics ovarian neoplasm prevent small hairpin RNA stem cell survival tumor tumor xenograft tumorigenic

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癌症高死亡率的两大因素上皮性卵巢癌（EOC）患者越来越明显地发现卵巢癌含有卵巢癌。具有增强的致瘤性和化疗耐药性的癌症干细胞 (CSC) 亚群。被认为是导致治疗失败和肿瘤复发的原因，但目前尚不清楚 CSCs 是如何造成的。在 DNA 损伤剂治疗中存活下来，以及存活的 CSC 再生肿瘤的过程易出错的跨损伤 DNA 合成 (TLS)，一种 DNA 损伤耐受机制绕过复制过程中的 DNA 损伤，已被认为可以介导获得性化学耐药性。最近的研究表明，卵巢 CSC 的 TLS 聚合酶 η (Polη) 表达升高；还证明 Polη 对顺铂治疗后卵巢 CSC 的存活至关重要。在此科学前提下，我们提出了一个假设，即 CSC 中增强的 Polη 介导的 TLS 有助于初始顺铂治疗后肿瘤复发和获得性顺铂耐药的发展促进 CSC 存活并增加 CSC 突变本提案的主要目标是确定。一种导致 EOC 复发和初始顺铂化疗耐药的新机制提出了两个具体目标来检验这一假设并实现我们的目标 1。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 对获得性顺铂耐药性发展的贡献 EOC 和顺铂诱导的卵巢 CSC 突变该提议的基本原理是：了解肿瘤复发和化疗耐药的机制将有助于我们期望开发新的治疗策略来改善 EOC 患者的预后。在该项目结束时，我们将提供确凿的证据，表明增强的表达卵巢 CSC 中的 Polη 有助于肿瘤的再生、CSC 的突变以及初始顺铂治疗后的顺铂耐药性，下调 Polη 将显着抑制肿瘤。复发并防止顺铂耐药性的发展，因此可用于新疗法 EOC 的战略。

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：
Oncotarget
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

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：
Cell death & disease
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

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：
PloS one
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

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：
International journal of oncology
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：
American journal of translational research
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