Intercepting novel functions of AURKA in gastric tumorigenesis

拦截 AURKA 在胃肿瘤发生中的新功能

• 批准号: 10663953
• 负责人: WAEL EL-RIFAI
• 金额: $ 43.54万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10663953
• 关键词: 20q; Ablation; Biological; Biological Factors; Biology; Cancer Biology; Cancer Etiology; Cancer Model; Cancer Patient; Carcinogens; Catchment Area; Cells; Cellular Stress; Cessation of life; Chemoresistance; Chronic; Clinical; Clinical Trials; Comprehensive Cancer Center; Diagnosis; Diagnostic; Environment; Epithelial Cells; Etiology; Eukaryotic Initiation Factor-4E; Florida; Genes; Genetically Engineered Mouse; Helicobacter Infections; Helicobacter pylori; Human; In Vitro; Incidence; Infection; Intercept; LGR5 gene; Mediating; Molecular; Oncogenic; Oncology; Organoids; Pathology; Population; Property; Proteins; Resistance; Rest; Risk Factors; Role; Sampling Studies; Signal Transduction; South America; Southeastern Asia; Stomach Carcinoma; Survival Rate; Technology; Testing; Therapeutic; Tissues; Translational Activation; Translations; Treatment Efficacy; United States; Universities; Work; aurora kinase A; carcinogenicity; chemotherapy; clinically relevant; docetaxel; evidence base; experience; fitness; functional outcomes; gastric carcinogenesis; gastric tumorigenesis; gastroesophageal cancer; human tissue; in vitro Model; in vivo; in vivo Model; malignant stomach neoplasm; mouse model; novel; overexpression; patient derived xenograft model; preclinical study; prognostic; protein expression; response; stem; therapy resistant; translational study; treatment response; tumorigenesis; tumorigenic

ABSTRACT/SUMMARY Gastric carcinoma (GAC) is the third most common cause of cancer-related death world-wide, causing more than 700,000 deaths each year. Unfortunately, the majority of gastric cancer patients are diagnosed at a late stage (Stage III or IV) in the United States, with a poor response to therapy and five-year survival rate of 5.2%. Infection with Helicobacter pylori (H. pylori), a type I carcinogen, is the main risk factor for gastric carcinogenesis. Infection with H. pylori creates a unique environment where epithelial cells must adapt to chronic cellular stress and are forced develop adaptive survival fitness properties that not only promote tumorigenesis but also resistance to chemotherapeutics. Understanding the molecular functions of carcinogenic biological factors such as H. pylori infection is a key step for developing evidence-based therapeutic approaches that are founded on the biology and molecular underpinning of gastric carcinogenesis. We have found that Aurora kinase A (AURKA) is a critical target at the 20q amplicon, overexpressed in approximately 60% of gastric cancers. We identified novel functions of AURKA in promoting EIF4E and cap- dependent translation of critical genes such as SOX9 and LGR5 that promote survival and expansion of tumorigenic cells in response to infection. We have also found that treatment-resistant cells were enriched for high levels of AURKA, SOX9, and LGR5. This proposal has three specific aims that include mechanistic, functional, and translational studies using unique in vitro and in vivo models, including organoid cultures and mouse models. In aim 1, we will investigate the mechanistic role of AURKA in reprogramming the translational machinery in response to infection with H. pylori. We will determine the AURKA-dependent functions in promoting gastric tumorigenesis and resistance to therapy, using in vivo models in Aim 2. The translational significance of our findings and therapeutic efficacy of targeting AURKA will be investigated in Aim 3. Upon completion of this work, we expect to unveil a new paradigm of cross-talk between AURKA and EIF4E- dependent translational machinery in promoting gastric tumorigenesis and resistance to therapy.

摘要/摘要 胃癌（GAC）是全球癌症相关死亡的第三大原因，导致更多 每年超过700,000人死亡。不幸的是，大多数胃癌患者被诊断出来 美国的阶段（第三阶段或IV期），对治疗的反应较差，五年生存率为5.2％。 幽门螺杆菌（H. Pylori）感染是I型致癌物，是胃的主要危险因素 致癌作用。幽门螺杆菌的感染创造了一个独特的环境，上皮细胞必须适应 慢性细胞应激，被迫发展自适应生存适应性，不仅促进 肿瘤发生，但也对化学治疗剂的抗性。了解 致癌生物学因素（例如幽门螺杆菌感染）是开发基于证据的关键步骤 建立在胃癌发生的生物学和分子基础上的治疗方法。 我们发现Aurora激酶A（Aurka）是20q Amplicon的关键目标，过表达 大约60％的胃癌。我们确定了Aurka在促进EIF4E和CAP-的新功能 关键基因（例如Sox9和Lgr5）的依赖性翻译，这些基因促进生存和膨胀 肿瘤细胞响应感染。我们还发现，耐药细胞富含 高水平的Aurka，Sox9和Lgr5。该提议具有三个特定目标，包括机械性， 使用独特体外和体内模型的功能和翻译研究，包括器官培养和 鼠标模型。在AIM 1中，我们将研究Aurka在重新编程中的机理作用 幽门螺杆菌感染的机械。我们将确定Aurka依赖性功能 在AIM 2中使用体内模型促进胃肿瘤发生和对治疗的抵抗力。 我们的发现和靶向Aurka的治疗功效的重要性将在AIM 3中进行研究。 完成这项工作，我们希望在Aurka和EIF4E-之间揭示一个新的跨讲话范式 促进胃肿瘤发生和对治疗的耐药性方面的依赖转化机制。