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.

肿瘤缓解和获得的化疗耐药性是两个主要因素，导致高死亡率 上皮卵巢癌（EOC）患者。越来越多的证据表明卵巢癌包含 癌细胞（CSC）的亚群，具有增强的肿瘤性和化学耐药性。这些CSC 据信负责治疗衰竭和肿瘤缓解。但是，目前尚不清楚CSC如何 生存DNA损害剂治疗，以及肿瘤如何通过生存CSC开发再生 化学抗性。容易出错的转移DNA合成（TLS），一种DNA损伤耐受性机制 复制过程中绕过DNA损伤，建议介导获得的化学抗性。我们的 最近的研究表明，卵巢CSC显示了TLS聚合酶η（Polη）的表达升高。 还表明，在顺铂治疗后，Polη对于卵巢CSC的存活至关重要。基于 这个科学的前提，我们产生了一个假设，即增强了CSC中的Polη介导的TLS有助于 肿瘤缓解和最初顺铂治疗后获得的顺铂耐药性的发展 促进CSC存活和增加CSC诱变。该提议的主要目的是确定 初始顺铂后有助于EOC继电器和化学治疗抗性的新型机制 治疗。提出了两个具体目标来检验这一假设并实现我们的目标。在特定目标1中，我们 将确定顺铂治疗后Polη介导的TLS对EOC继电器的贡献。在特定的目标2中， 我们将描述Polη介导的TLS对获得的顺铂抗性的发展的贡献 EOC和顺铂诱导的卵巢CSC突变。根据该提议的理由是 了解肿瘤缓解和抗化疗的基础机制将有助于 开发新的疗法策略以改善EOC患者的结果。我们的期望是 在该项目的结论中，我们将提供可靠的证据，表明增强的表达 卵巢CSC中的polη有助于肿瘤调节，CSC中的诱变和发展 初次顺铂治疗后的顺铂耐药性。 polη下调会显着抑制肿瘤 继电器并防止顺铂耐药性的发展，因此可以探索新疗法 EOC的策略。

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

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.

• 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