Targeting chemotherapy resistant high grade serous ovarian cancer

项目摘要 在所有妇科癌症中，卵巢癌(OCA)的死亡率在美国最高。浆液性血液病患者 OCA对目前的治疗方法有反应，包括细胞毒治疗和手术。但大约90%的患者 复发，他们不可避免地会死于一种对化疗有抗药性的疾病。白血病抑制因子 (Lif)，属于白介素6家族的一种细胞因子，它通过糖蛋白130(Gp130)和 生活情结。我使用肿瘤在线数据库进行的初步研究表明，LIF强烈表达 在OCA组织中，LIF和LIFR的表达水平显著高于正常组织 化疗无应答者与应答者相比。此外，我对条件培养液和 从18个不同的OCA细胞收集的细胞裂解物证实存在LIF和LIFR的自分泌环 亚奥理事会。然而，靶向LIFR轴治疗化疗耐药的机制和治疗作用 仍然未知，这是一个重大的知识差距，这一前提将在F99阶段得到检验。在F99 阶段，我将测试LIF/LIFR信号中断将使耐药细胞对 化疗和LIFR抑制剂的维持治疗将延缓化疗耐药。 具体地说，我将确立LIFR轴在促进化疗方面的意义和机制 用CRISPR KO和全球基因组方法研究浆液性OCA细胞的耐药性。我要测试一下LIFR的效用 使用患者来源的抑制剂EC359治疗/预防化疗耐药的发展 器官移植(PDO)和异种移植(PDX)模型。较大肿瘤所经历的低氧环境 降低化疗反应，并因腹水加重。低氧诱导因子(HIF) 被癌细胞激活，以刺激血管生成，控制细胞代谢，促进细胞 生长是抵御低氧压力的一种防御机制。此外，缺氧还反式激活了两种功能 LIF启动子内的低氧反应元件并诱导LIF表达。两者之间存在着一种关系 OCA干细胞(CSCs)与肿瘤化疗耐药性和复发抗血管生成治疗耐药和 低氧对卵巢CSCs的化疗耐药均有影响。总而言之，这些最新的发现意味着 缺氧的肿瘤微环境增加了HIFs、LIF和外排转运蛋白的表达，AS 以及CSCs中化疗耐药的发展。在K00阶段，我将把我的培训扩展到以下领域 低氧介导的干细胞、上皮间质转化(EMT)和治疗耐药。具体来说，我 将确定低氧和LIF/LIFR轴诱导EMT和茎的机制，并建立 低氧-LIF/LIFR轴在OCA靶向治疗耐药中的意义建议数 对F99/K00的研究具有重要的临床意义，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确立LIFR作为一种新的治疗方法 OCA的治疗靶点。

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.