Averting recurrent and resistant ovarian tumors

避免复发性和耐药性卵巢肿瘤

• 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
• 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

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

Depleting ovarian cancer stem cells with calcitriol.

• DOI: 10.18632/oncotarget.24520
• 发表时间: 2018-03-06
• 期刊: Oncotarget
• 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: 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

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

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.

• 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