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

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

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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.

项目摘要在2021年，据估计将在联合诊断出149,480例新的结肠癌病例州和52,980例CRC患者将死于这种疾病，其中事件和死亡仅略有与男性相比，女性较低。早期诊断和改进的治疗方法减少了美国的CRC；但是，这种疾病的全球率正在增加，尤其是在发展国家。患有结肠癌或遗传基因突变家族史的人有很高的风险但是，开发CRC，据估计，所有情况中有60-65％是“零星”，没有遗传或遗传背景中的风险因素。零星CRC的一些风险因素由许多其他癌症，这包括年龄，但还包括其他可预防的因素，例如肥胖，久坐的生活方式，吸烟，低纤维/高脂肪饮食，饮酒和红肉的高摄入量。另一个子类CRC患者是年轻人吗？该组中的疾病事件一直在增加收入发达国家。对于许多结肠癌患者而言，手术是主要的第一选择，这也可以是伴随或之前进行辐射和新辅助治疗。高风险患者III和IV颜色癌症用各种药物组合治疗，包括氟尿嘧啶，白细胞蛋白，叶酸，奥沙利铂和卡培他滨抑制疾病复发的风险。除了细胞毒性药物疗法之外靶向特定基因（例如EGFR和途径）（血管生成）的医学方法正在与免疫疗法一起开发。拟议的研究将侧重于潜在机制和衍生的BIS-diend（CDIMS）的临床应用，结合了孤儿核接收器4A1（NR4A1，NR4A1， Nur77）。 NR4A1在结肠癌患者中过表达，不仅调节了促疾病的表达基因和途径，但也可以在肿瘤浸润淋巴细胞。初步研究证实CDIM/NR4A1拮抗剂都表现出化学治疗活性，但也下调了PD-L1和反向T细胞疲惫，并提出了拟议的研究 AIM 1将使用体外细胞培养和合成小鼠模型来确定潜在机制（AIM 1）。在AIM 2中，将研究CDIM/NR4A1拮抗剂的化学治疗和免疫学作用可诱导的APC敲除小鼠模型，在与全身和肠道特异性NR4A1交叉的小鼠中删除。这些研究，再加上循环干细胞的组织学分析以及单细胞分析肿瘤微环境和免疫系统将确认NR4A1作为重要的新兴药物的作用结肠癌化学和免疫疗法的靶标。