Averting recurrent and resistant ovarian tumors

肿瘤复发和获得性化疗耐药是导致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 具有增强的致瘤性和化疗耐药性的癌症干细胞(CSCs)亚群。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CSC是如何 幸存的DNA损伤剂治疗，以及幸存的CSCs如何再生肿瘤 化疗耐药。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，已被认为是介导获得性化疗耐药的原因。我们的 最近的研究表明，卵巢上皮样干细胞表现出Tls聚合酶η(Polη)的高表达； 同时也证明了POLη对于顺铂治疗后卵巢CSCs的存活至关重要。基于 在这一科学前提下，我们提出了一个假设，即增强的POLη介导的CSCs中的TLS有助于 顺铂初始治疗后肿瘤复发和获得性顺铂耐药性的发展 促进CSC存活，增加CSC诱变。这项提案的主要目标是确定 顺铂治疗后卵巢癌复发和化疗耐药的新机制 治疗。为了检验这一假设并实现我们的目标，本文提出了两个具体的目标。在具体目标1中，我们 将确定POLη介导的TLS在顺铂治疗后卵巢癌复发中的作用。在具体目标2中， 我们将描述POLη介导的TLS在获得性顺铂耐药中的作用。 EoC和顺铂诱导的卵巢CSCs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卵巢癌患者的预后。我们的期望是 在本项目结束时，我们将提供确凿的证据，表明增强的 卵巢肿瘤干细胞中的POLη在肿瘤的再生长、突变和肿瘤的发生中起重要作用。 顺铂初始治疗后耐药。Polη的下调将显著抑制肿瘤 预防和复发顺铂耐药，可作为一种新的治疗方法。 面向EoC的战略。

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.