Targeting chemotherapy resistant high grade serous ovarian cancer

靶向化疗耐药的高级别浆液性卵巢癌

基本信息

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
项目类别：
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

项目摘要

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.

项目概要在所有妇科癌症中，卵巢癌（OCa）在美国死亡率最高。浆液性患者 OCa 对当前的治疗有反应，包括细胞毒治疗和手术。但大约90%的患者复发，并且他们不可避免地会因化疗耐药的疾病而去世。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 (gp130) 和 LIFR 复合体。我使用肿瘤在线数据库进行的初步研究表明，LIF 强表达与正常组织相比，OCa 中 LIF 和 LIFR 的表达水平显着更高化疗无反应者与反应者相比。此外，我对条件培养基的分析和从 18 个不同的 OCa 细胞收集的细胞裂解物证实了 LIF 和 LIFR 的自分泌环的存在奥卡。然而，靶向LIFR轴治疗化疗耐药的机制和治疗效用仍然未知，代表着一个重大的知识差距，这个前提将在 F99 阶段进行测试。在F99中阶段，我将测试以下假设：LIF/LIFR 信号传导的破坏会使耐药细胞对化疗和 LIFR 抑制剂维持治疗将延缓化疗耐药。具体来说，我将建立LIFR轴在促进化疗中的意义和机制使用 CRISPR KO 和全局基因组方法检测浆液性 OCa 细胞的耐药性。我将测试 LIFR 的实用性抑制剂 EC359 使用患者来源的药物治疗/预防化疗耐药性的发展类器官（PDO）和异种移植（PDX）模型。较大肿瘤经历的缺氧环境降低化疗反应并因腹水而加剧。缺氧诱导因子（HIF）被癌细胞激活，刺激血管生成，控制细胞代谢，促进细胞生长生长作为对抗缺氧应激的防御机制。此外，缺氧会反式激活两种功能 LIF 启动子内的缺氧反应元件并诱导 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的化疗耐药性均受到缺氧的影响。总之，这些最近的发现意味着缺氧的肿瘤微环境会增加 HIF、LIF 和外排转运蛋白的表达，如以及 CSC 化疗耐药性的发展。在K00阶段，我将把我的训练扩展到以下领域：缺氧介导的干性、上皮间质转化（EMT）和治疗抵抗。具体来说，我将定义缺氧和 LIF/LIFR 轴诱导 EMT 和干性的机制，并建立缺氧-LIF/LIFR 轴在 OCa 对靶向治疗耐药的发展中的重要性。拟议的 F99/K00 的研究具有重要的临床意义，因为它将定义 LIFR 轴在 OCa 中的重要性进展、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 OCa 治疗的目标。