Targeting chemotherapy resistant high grade serous ovarian cancer

项目摘要 在所有妇科癌症中，卵巢癌（OCa）在美国的死亡率最高。浆液性 OCa对目前的治疗有反应，包括细胞毒性治疗和手术。但大约90%的患者 复发，并且他们不可避免地死于化学抗性的疾病。白血病抑制因子 (LIF)是一种属于白细胞介素-6家族的细胞因子，它通过糖蛋白130（gp 130）和 LIFR复合体。我使用肿瘤在线数据库进行的初步研究显示，LIF强烈表达于 与正常组织相比，OCa中LIF和LIFR的表达水平显著高于OCa中的表达水平。 化疗无应答者与应答者相比。此外，我对条件培养基和 从18个不同的OCa细胞收集的细胞裂解物证实了在OCa细胞中存在LIF和LIFR的自分泌环。 OCa。然而，靶向LIFR轴治疗化疗耐药的机制和治疗效用尚不清楚。 仍然未知，这代表了一个重大的知识差距，这一前提将在F99阶段进行测试。在F99中 在第一阶段，我将检验LIF/LIFR信号转导的破坏将使抗性细胞对 LIFR抑制剂维持治疗可延缓化疗耐药。 具体而言，本研究将探讨LIFR轴在促进化疗中的意义和作用机制 使用CRISPR KO和全局基因组方法在浆液性OCa细胞中的抗性。我将测试LIFR的效用 抑制剂EC 359用于治疗/预防化疗耐药性发展 类器官（PDO）和异种移植（PDX）模型。大肿瘤所经历的缺氧环境 降低化疗反应并因腹水而加重。缺氧诱导因子 被癌细胞激活，以刺激血管生成，控制细胞代谢，并促进细胞增殖。 生长作为对缺氧应激的防御机制。此外，缺氧反式激活两种功能性 LIF启动子内的低氧应答元件并诱导LIF表达。之间存在关系 OCa干细胞（CSC）与肿瘤化疗耐药性和复发。抗血管生成治疗耐药性和 卵巢CSCs的化疗耐药性均受缺氧的影响。总之，这些最新的发现表明， 缺氧肿瘤微环境增加了HIF、LIF和外排转运蛋白的表达， 以及CSC中化学抗性的发展。在K 00阶段，我将把我的培训扩展到以下领域 缺氧介导的干性、上皮间质转化（EMT）和治疗抗性。我特别 将定义缺氧和LIF/LIFR轴诱导EMT和干性的机制，并建立 缺氧-LIF/LIFR轴在OCa靶向治疗耐药发展中的意义。拟议 F99/K 00的研究在临床上很重要，因为它将确定LIFR轴在OCa中的意义 进展、化疗和抗血管生成治疗耐药性，并将LIFR确立为一种新型治疗方法 治疗OCa的目标。

Project Summary Of all gynecologic cancers, ovarian cancer (OCa) has the highest mortality rate in the US. Patients with serous OCa respond to current treatments, including cytotoxic therapy and surgery. But about 90% of patients have recurrence, and they inevitably pass away from a disease that is chemoresistant. Leukemia inhibitory factor (LIF), a cytokine that belongs to the interleukin-6 family, and it signals through the glycoprotein 130 (gp130) and LIFR complex. My preliminary research using tumor online data bases revealed that LIF is strongly expressed in OCa compared to normal tissues, and expression levels of LIF and LIFR were significantly greater in chemotherapy non-responders as compared to responders. Further, my analyses of conditioned medium and cell lysates collected form 18 different OCa cells confirmed existence of autocrine loops of LIF and LIFR in OCa. However, the mechanisms and therapeutic utility of targeting LIFR axis to treat chemotherapy resistance remain unknown, representing a major knowledge gap and this premise will be tested in F99 phase. In F99 phase, I will test the hypothesis that disruption of LIF/LIFR signaling will sensitize resistant cells to chemotherapy, and maintenance therapy with LIFR inhibitor will delay chemotherapy resistance. Specifically, I will establish the significance and mechanisms of LIFR axis in promoting chemotherapy resistance in serous OCa cells using CRISPR KO and global genomic approaches. I will test the utility of LIFR inhibitor EC359 in treating/preventing development of chemotherapy resistance using patient derived organoid (PDO) and xenograft (PDX) models. The hypoxic circumstances that bigger tumors experience decrease chemotherapy response and are exacerbated by ascites. Hypoxia inducible factors (HIFs) are activated by cancer cells to stimulate vasculogenesis, control cell metabolism, and promote cell growth as a defense mechanism against hypoxic stress. Moreover, hypoxia transactivates two functional hypoxia responsive elements within LIF promoter and induces LIF expression. There is a relationship between OCa Stem Cells (CSCs) and tumor chemoresistance and recurrence. Antiangiogenic treatment resistance and chemoresistance of ovarian CSCs are both influenced by hypoxia. Together, these recent findings imply that the hypoxic tumor microenvironment increases the expression of HIFs, LIF, and efflux transporters, as well as development of chemoresistance in CSCs. In the K00 phase, I will expand my training into the area of hypoxia mediated stemness, epithelial mesenchymal transition (EMT) and therapy resistance. Specifically, I will define the mechanisms by which hypoxia and LIF/LIFR axis induce EMT and stemness and establish the significance of hypoxia-LIF/LIFR axis in the development of OCa resistance to targeted therapy. The proposed research in F99/K00 is clinically important because it will define the significance of LIFR axis in OCa progression, chemotherapy and antiangiogenic therapy resistance and establish LIFR as a novel therapeutic target for the treatment of OCa.