NR4A1 Antagonists Inhibit Colorectal Cancer Growth and Enhance Immune Surveillance

NR4A1 拮抗剂抑制结直肠癌生长并增强免疫监视

基本信息

批准号：
10587593
负责人：
MAEN ABDELRAHIM
金额：
$ 58.56万
依托单位：
TEXAS A&M UNIVERSITY
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：
2023-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587593
关键词：
Affinity Age Alcohol consumption Antibodies Binding Cell Culture Techniques Cells Cessation of life Chemopreventive Agent Chemotherapy-Oncologic Procedure Colon Colon Carcinoma Colonic Neoplasms Colorectal Cancer Complement 2 Complex Coupled Cytotoxic agent DNA Sequence Alteration Developed Countries Developing Countries Development Disease Distal Drug Combinations Drug Targeting Drug usage ERBB2 gene Early Diagnosis Epidermal Growth Factor Receptor Exhibits Family history of Fluorouracil Generations Genes Genetic Growth Histologic Human Immune checkpoint inhibitor Immune system Immunologic Surveillance Immunologics Immunosuppression Immunotherapeutic agent Immunotherapy In Vitro Incidence Income Individual Indoles Infection Inherited Intake Intestines Invaded KDR gene Knockout Mice Laboratories Leucovorin Ligands Link Location Malignant Neoplasms Meat Modeling Molecular Mus NR4A1 gene NR4A2 gene Neoadjuvant Therapy Nuclear Orphan Receptor Obesity Oncogenic Operative Surgical Procedures Pathologic Pathway interactions Patients Pharmacotherapy Phosphotransferases Play Radiation Rectal Cancer Recurrent disease Regulation Research Risk Factors Role Sampling Smoking T-Lymphocyte Therapeutic Time Tumor stage Tumor-Infiltrating Lymphocytes United States Vascular Endothelial Growth Factors Woman Xenograft procedure angiogenesis antagonist cancer cell cancer diagnosis capecitabine cell growth chemotherapeutic agent chemotherapy clinical application colon cancer patients colorectal cancer treatment dietary disorder risk early screening exhaustion genetic risk factor high risk high-fat/low-fiber diet improved lifestyle factors men mortality mouse model neoplastic cell overexpression oxaliplatin precision medicine programmed cell death ligand 1 receptor sedentary lifestyle sex single cell analysis stem cells therapeutic effectiveness tumor tumor growth tumor microenvironment young adult

项目摘要

PROJECT SUMMARY In 2021, it is estimated that there will be 149,480 new cases of colon cancer diagnosed in the United States and 52,980 CRC patients will die from this disease in which the incidence and death are only slightly lower in women compared to men. Early diagnosis and improved treatments have decreased the incidence of CRC in the United States; however, global rates of this disease are increasing, particularly in developing countries. Individuals with a family history of colon cancer or inherited genetic mutations have a high risk for developing CRC, however, it is estimated that 60-65% of all cases are “sporadic” with no inherited or genetic risk factors in their background. Some of the risk factors for the sporadic CRCs are shared by many other cancers and this includes age but also other preventable factors such as obesity, sedentary lifestyle, smoking, low fiber/high fat diets, alcohol consumption and high intakes of red meat. Another sub-class of CRC patients are young adults and the incidence of disease among this group has been increasing particularly in high income developed countries. Surgery is a major first option for many colon cancer patients and this can also be accompanied or preceded by radiation and neoadjuvant therapy. High risk patients with stage III and IV colon cancer are treated with various drug combinations including fluorouracil, leucovorin, folinic acid, oxaliplatin and capecitabine which inhibit the risk of disease recurrence. In addition to cytotoxic drug therapies more precision medicine approaches that target specific genes such as EGFR and pathways (angiogenesis) are being developed along with immunotherapies. The proposed research will focus on potential mechanisms and clinical applications of bis-indole derived (CDIMs) agents that bind the orphan nuclear receptor 4A1 (NR4A1, Nur77). NR4A1 is overexpressed in colon cancer patients and regulates expression not only of pro-oncogenic genes and pathways but also PD-L1 and genes associated with T-cell exhaustion that can be identified in tumor infiltrating lymphocytes. Preliminary studies confirm that CDIM/NR4A1 antagonists exhibit both chemotherapeutic activity but also downregulate PD-L1 and reverse T-cell exhaustion and proposed studies in Aim 1 will determine the underlying mechanisms using in vitro cell culture and syngeneic mouse models (Aim 1). In Aim 2 the chemotherapeutic and immunologic effects of CDIM/NR4A1 antagonists will be investigated in an inducible APC knockout mouse model and in mice crossed with whole body and intestinal specific NR4A1 deletion. These studies, coupled with histological analysis of cycling stem cells and single cell analysis of the tumor microenvironment and immune system will confirm the role of NR4A1 as an important emerging drug target for both colon cancer chemo- and immune therapies.

项目概要 2021年，预计美国将新诊断出149,480例结肠癌病例各州和 52,980 名 CRC 患者将死于这种疾病，其中发病率和死亡人数仅轻微与男性相比，女性的发病率较低。早期诊断和改进的治疗降低了该病的发病率。然而，美国的结直肠癌发病率正在上升，特别是在发展中国家有结肠癌家族史或遗传性基因突变的个人患结肠癌的风险很高。然而，据估计，60-65% 的 CRC 病例是“散发性”的，没有遗传性或遗传性散发性结直肠癌的一些危险因素是许多其他人所共有的。癌症，这包括年龄，还包括其他可预防的因素，如肥胖、久坐的生活方式、吸烟、低纤维/高脂肪饮食、饮酒和大量摄入红肉是结直肠癌患者的另一个亚类。是年轻人，该群体的疾病发病率一直在增加，特别是在高收入人群中收入发达国家。手术是许多结肠癌患者的主要首选选择，这也可以是伴随或之前进行放射和新辅助治疗的 III 期和 IV 期结肠高危患者。癌症采用多种药物组合治疗，包括氟尿嘧啶、亚叶酸、亚叶酸、奥沙利铂和卡培他滨除了细胞毒药物治疗外更能抑制疾病复发的风险。针对特定基因（例如 EGFR）和通路（血管生成）的医学方法正在研究中与免疫疗法一起开发的研究将集中于潜在的机制和结合核孤儿受体 4A1（NR4A1， Nur77）。NR4A1 在结肠癌患者中过度表达，并且不仅调节促癌基因的表达。基因和通路，还有 PD-L1 和与 T 细胞耗竭相关的基因，这些基因可以在初步研究证实 CDIM/NR4A1 拮抗剂具有这两种作用。化疗活性，还下调 PD-L1 并逆转 T 细胞耗竭，并提出了以下研究：目标 1 将使用体外细胞培养和同基因小鼠模型确定潜在机制（目标 1) 在目标 2 中，将研究 CDIM/NR4A1 拮抗剂的化疗和免疫作用。诱导型 APC 敲除小鼠模型以及与全身和肠道特异性 NR4A1 杂交的小鼠这些研究结合循环干细胞的组织学分析和单细胞分析。肿瘤微环境和免疫系统将证实NR4A1作为重要新兴药物的作用结肠癌化疗和免疫疗法的目标。