Intercepting novel functions of AURKA in gastric tumorigenesis

拦截 AURKA 在胃肿瘤发生中的新功能

基本信息

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
项目类别：
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

项目摘要

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/总结胃癌 (GAC) 是全球第三大癌症相关死亡原因，导致更多人死亡每年有超过 70 万人死亡。不幸的是，大多数胃癌患者确诊时已属晚期。在美国，该疾病处于Ⅲ期或Ⅳ期，治疗反应较差，五年生存率为5.2%。幽门螺杆菌（H. pylori）是一种I型致癌物，感染是胃病的主要危险因素。致癌作用。幽门螺杆菌感染创造了一个独特的环境，上皮细胞必须适应这个环境慢性细胞压力，被迫发展适应性生存健身特性，不仅促进肿瘤发生，而且对化疗药物产生耐药性。了解分子功能幽门螺杆菌感染等致癌生物因素是开发循证证据的关键一步基于胃癌发生的生物学和分子基础的治疗方法。我们发现极光激酶 A (AURKA) 是 20q 扩增子的关键靶标，在约占胃癌的60%。我们确定了 AURKA 在促进 EIF4E 和 cap- 方面的新功能 SOX9 和 LGR5 等关键基因的依赖翻译可促进细胞的存活和扩张致瘤细胞对感染的反应。我们还发现，治疗抵抗细胞被富集高水平的 AURKA、SOX9 和 LGR5。该提案具有三个具体目标，包括机械、使用独特的体外和体内模型进行功能和转化研究，包括类器官培养和鼠标模型。在目标 1 中，我们将研究 AURKA 在重编程翻译过程中的机制作用应对幽门螺杆菌感染的机制。我们将确定 AURKA 依赖的函数使用目标 2 中的体内模型促进胃肿瘤发生和对治疗的耐药性。我们的研究结果的意义和靶向 AURKA 的治疗效果将在目标 3 中进行研究。完成这项工作后，我们期望揭开 AURKA 和 EIF4E 之间串扰的新范式—— 促进胃肿瘤发生和治疗耐药性的依赖翻译机制。