Targeting chemotherapy resistant high grade serous ovarian cancer

靶向化疗耐药的高级别浆液性卵巢癌

• 批准号: 10744479
• 负责人: Behnam Ebrahimi
• 金额: $ 3.65万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-16 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10744479
• 关键词: ABCG2 gene; Affect; Angiogenesis Inhibitors; Area; Ascites; Autocrine Communication; Award; Cancer Patient; Caring; Cells; Cellular Metabolic Process; Chemoresistance; Chemotherapy-Oncologic Procedure; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Colorectal Cancer; Complex; Conditioned Culture Media; Cytotoxic Chemotherapy; Databases; Defense Mechanisms; Development; Disease; Disease Resistance; Doxorubicin; Epithelium; FRAP1 gene; Family; Gene Expression; Genetic; Genomic approach; Grant; Human; Hypoxia; Hypoxia Inducible Factor; Hypoxia-Responsive Elements; Interleukin-6; Knowledge; LIF gene; LIFR gene; Link; MAP Kinase Gene; Maintenance Therapy; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of pancreas; Mediating; Mesenchymal; Normal tissue morphology; Operative Surgical Procedures; Organoids; Ovarian; Pathway interactions; Patients; Phase; Proliferating; Proto-Oncogene Proteins c-akt; Publishing; Recurrence; Recurrent Malignant Neoplasm; Research; Research Personnel; Resistance; Resistance development; Role; STAT3 gene; Serous; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Training; Tumor Tissue; United States; Xenograft Model; autocrine; cancer cell; cancer recurrence; cancer stem cell; cancer therapy; career; cell growth; chemotherapy; clinically relevant; cytokine; experience; glycoprotein 130; inhibitor; member; mortality; mouse model; new therapeutic target; prevent; promoter; response; standard of care; stemness; targeted treatment; therapy resistant; treatment response; tumor; tumor hypoxia; tumor microenvironment; tumor progression; vasculogenesis

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.

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。浆液的患者 OCA应对当前治疗，包括细胞毒性疗法和手术。但是约有90％的患者患有 复发，它们不可避免地摆脱了化学抗性的疾病。白血病抑制因素 （LIF），属于白介素6家族的细胞因子，以及通过糖蛋白130（GP130）和 LIFR复合体。我使用肿瘤在线数据基础的初步研究表明，LIF强烈表达 与正常组织相比，在OCA中，LIF和LIFR的表达水平明显更高 与反应者相比，化学疗法无反应。此外，我对条件培养基和 细胞裂解物收集的18种不同的OCA细胞证实存在LIF和LIFR的自分泌环中存在 OCA。但是，靶向LIFR轴的机制和治疗效用以治疗化学疗法耐药性 保持未知，代表主要的知识差距，该前提将在F99阶段进行测试。在F99中 阶段，我将测试以下假设：LIF/LIFR信号的破坏将使抗性细胞敏感到 化学疗法和使用LIFR抑制剂维持治疗将延迟化学疗法抗性。 具体而言，我将确定LIFR轴上在促进化学疗法中的重要性和机制 使用CRISPR KO和全球基因组方法在浆液OCA细胞中的抗性。我将测试LIFR的效用 抑制剂EC359在使用患者衍生的患者治疗/预防化学疗法耐药性方面 器官（PDO）和异种移植（PDX）模型。较大肿瘤经历的低氧环境 减少化学疗法反应，并通过腹水加剧。低氧诱导因子（HIF） 被癌细胞激活以刺激血管生成，控制细胞代谢并促进细胞 增长是防御低氧应激的防御机制。此外，缺氧可以反式激活两个功能 LIF启动子内的缺氧反应元素并诱导LIF表达。之间有关系 OCA干细胞（CSC）和肿瘤化学抗性和复发。抗血管生成治疗耐药性和 卵巢CSC的化学耐药性都受到缺氧的影响。这些最近的发现意味着 低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K00阶段，我将把培训扩展到 缺氧介导的干性，上皮间质转变（EMT）和耐药性。具体来说，我 将定义缺氧和LIF/LIFR轴诱导EMT和茎的机制，并确定 低氧/LIFR轴对OCA对靶向治疗的耐药性的意义。提议 F99/K00的研究在临床上很重要，因为它将定义LIFR轴对OCA的重要性 进展，化学疗法和抗血管生成疗法耐药性，并将LIFR确立为一种新型治疗 OCA治疗的目标。