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

• 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
• 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

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.

项目总结 据估计，到2021年，美国将新增149,480例结肠癌确诊病例 各州和52,980名结直肠癌患者将死于这种发病率和死亡率仅为轻微的疾病 女性比男性低。早期诊断和改进的治疗方法降低了该病的发病率 在美国；然而，这种疾病的全球发病率正在上升，特别是在发展中国家 国家。有结肠癌家族史或遗传基因突变的个体患结肠癌的风险很高。 然而，据估计，所有病例中有60%-65%是散发性的，没有遗传性或遗传性 他们背景中的风险因素。散发性癌的一些危险因素与其他许多疾病有共同之处 癌症，这包括年龄，但也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，饮酒和高红肉摄入量。结直肠癌患者的另一亚类 是年轻人吗？这一群体的发病率一直在上升，特别是在 收入发达国家。手术是许多结肠癌患者的主要首选，这也可以是 伴随或先于放射和新辅助治疗。III期和IV期结肠癌高危患者 治疗癌症的药物组合包括氟尿嘧啶、亚叶酸钙、亚叶酸、奥沙利铂和 卡培他滨可抑制疾病复发的风险。除了细胞毒性药物治疗外，还可以更精确地 针对特定基因，如EGFR和通路(血管生成)的药物方法正在进行中 是随着免疫疗法一起发展起来的。拟议的研究将侧重于潜在的机制和 结合孤儿核受体4A1的双吲哚衍生物(CDIMs)的临床应用 (Nur77)。NR4A1在结肠癌患者中过表达，不仅调节癌前基因的表达 基因和途径，以及PD-L1和与T细胞衰竭相关的基因，可以在 肿瘤浸润性淋巴细胞。初步研究证实CDIM/NR4A1拮抗剂既表现出 化疗活性，但也下调PD-L1和逆转T细胞耗竭 AIM 1将使用体外细胞培养和同基因小鼠模型(AIM)来确定潜在的机制 1)。在目标2中，将研究CDIM/NR4A1拮抗剂的化疗和免疫学作用 一种可诱导的APC基因敲除小鼠模型及其与全身和肠道特异性NR4A1杂交小鼠的研究 删除。这些研究，再加上对循环干细胞的组织学分析和对 肿瘤微环境和免疫系统将确认NR4A1作为重要新兴药物的作用 结肠癌化疗和免疫治疗的靶点。