TASK ORDER: PRECLINICAL TESTING OF CD73 INHIBITORS FOR PANCREATIC CANCER IMMUNOPREVENTION

任务顺序：CD73 抑制剂用于胰腺癌免疫预防的临床前测试

• 批准号: 10269157
• 负责人: POWEL BROWN
• 金额: $ 38.89万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-21 至 2021-09-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10269157
• 关键词: 5' -Nucleotidase; ADORA3 gene; Adenosine; Adenosine Monophosphate; Biological Markers; Cells; Cessation of life; Clinical Trials; Data; Development; Diagnosis; Disease Progression; Dose; Early Intervention; Environment; Enzymes; Epithelial; Epithelial Cells; Epithelium; Financial Hardship; G-Protein-Coupled Receptors; Genes; Genetically Engineered Mouse; Goals; Growth; Hidrocystoma; Human; Human Genetics; Hypoxia; Immune; Immunologic Surveillance; Immunosuppression; Incidence; Individual; Inflammation; Inflammatory; Intercept; Intervention; Isogeneic graft; Lesion; Malignant Neoplasms; Malignant neoplasm of pancreas; Molecular Genetics; Monoclonal Antibodies; Mucinous Neoplasm; Natural Killer Cells; Oncogenic; Pancreas; Pancreatic Intraepithelial Neoplasia; Preclinical Testing; Prevention; Purinergic P1 Receptors; Regimen; Schedule; Signal Pathway; Signal Transduction; Solid Neoplasm; Stromal Cells; Survival Rate; T-Lymphocyte; Testing; Time; Translating; adenosine monophosphate-adenosine; base; cancer prevention; clinical effect; clinically relevant; cytotoxicity; effector T cell; extracellular; improved; in vivo; inhibitor/antagonist; mortality; mouse model; neoplastic; outcome forecast; overexpression; pancreatic cancer patients; prevent; small molecule; targeted agent; targeted treatment; trend; tumor; tumor growth; tumor progression

Pancreatic cancer (PC) is a highly aggressive cancer usually diagnosed at an advanced stage and has the worst prognosis of any cancer. Almost 57,600 individuals will be diagnosed with PC, with ~47,050 deaths expected, in the US alone in 2020. Although PC accounts for only about 3% of all cancers in the US, it accounts for about 7% of all cancer deaths. Moreover, recent incidence and mortality rates suggest an increasing trend of PC. Lack of effective early interventions are major factors contributing to the poor prognosis and dismal survival rates of PC patients. Despite many advances in the molecular genetics of human pancreatic cancers, targeted therapies have not yet translated to improved overall survival. Recent developments demonstrate that pre-invasive precursors, such as pancreatic intraepithelial neoplasia (PanINs), intrapapillary mucinous neoplasms (IPMNs), and cystadenomas, progress slowly over many years before developing into invasive PC. Yachida et al. has estimated that there is a window of opportunity of ~10 years from the moment a pancreatic epithelial cell gets an oncogenic hit to the time of diagnosis, which can be exploited to implement early intervention strategies. Hence, developing cancer prevention and interception strategies such as immunoprevention that delay/inhibit/prevent the formation and/or progression of pre-invasive lesions to PC is of utmost importance as if successful, it offers enormous potential for increasing the survival and lowering the societal financial burden. The adenosine signaling pathway, especially in the context of increased extracellular adenosine, is an important driver of tumor progression. Adenosine signaling is a mechanism that cells utilize to reduce inflammation in inflammatory and hypoxic environments. 5′-nucleotidase, also known as ecto-5′-nucleotidase or CD73, an enzyme that in humans encoded by the NT5E gene converts extracellular adenosine monophosphate (AMP) into immunosuppressive adenosine, which shuts down anti-tumor immune surveillance. Adenosine signals via adenosine receptors to promote immune suppression. There are four subtypes of adenosine receptors (A1A, A2A, A2B and A3AR), all of which are G protein coupled receptors (GPCR) and can be co-expressed on stromal and epithelial cells (10). CD73 can also be expressed on effector T cells. Emerging data in a number of solid tumors including PC demonstrates that CD73 overexpressed on neoplastic epithelium generates extracellular adenosine from AMP, which inhibits T cell and NK cell cytotoxicity, enabling tumor growth and disease progression. The importance of CD73 in PC growth is well established. These immunosuppressive and tumor promoting functions of CD73 make it an appealing target for prevention and treatment of pancreatic cancer. There are several clinical trials testing CD73-targeting agents, including small molecule CD73 inhibitors and anti-CD73 monoclonal antibody, based on the rationale that inhibition of CD73 activity may enhance anti-tumor immune surveillance at the level of T cells and other immune cells regulated by adenosine thereby delaying PC development. The overall goal of the project is to evaluate immunopreventive effects of clinically relevant small molecule CD73 inhibitors in pancreatic cancer syngraft and genetically engineered mouse models that recapitulate human pancreatic cancer progression.

胰腺癌（PC）是一种高度侵袭性的癌症，通常在晚期才被诊断出来，并且是所有癌症中预后最差的。 2020 年，仅在美国，就有近 57,600 人被诊断患有 PC，预计约有 47,050 人死亡。尽管 PC 只占美国所有癌症的 3% 左右，但它却占所有癌症死亡人数的 7% 左右。此外，最近的发病率和死亡率表明 PC 呈上升趋势。缺乏有效的早期干预是导致PC患者预后不良和生存率低的主要因素。尽管人类胰腺癌的分子遗传学取得了许多进展，但靶向治疗尚未转化为改善总体生存率。最近的发展表明，侵袭前的前体细胞，如胰腺上皮内瘤变 (PanIN)、乳头内粘液性肿瘤 (IPMN) 和囊腺瘤，在发展为侵袭性 PC 之前会经过多年缓慢进展。矢田等人。据估计，从胰腺上皮细胞受到致癌打击到诊断时，有大约 10 年的机会窗口，可以利用这个机会实施早期干预策略。因此，制定癌症预防和拦截策略（例如免疫预防）来延迟/抑制/预防 PC 浸润前病变的形成和/或进展至关重要，因为如果成功的话，它为提高生存率和降低社会经济负担提供了巨大的潜力。腺苷信号通路，特别是在细胞外腺苷增加的情况下，是肿瘤进展的重要驱动因素。腺苷信号传导是细胞用来减少炎症和缺氧环境中炎症的机制。 5'-核苷酸酶，也称为 ecto-5'-核苷酸酶或 CD73，是一种在人体中由 NT5E 基因编码的酶，可将细胞外单磷酸腺苷 (AMP) 转化为免疫抑制腺苷，从而关闭抗肿瘤免疫监视。腺苷通过腺苷受体发出信号以促进免疫抑制。腺苷受体有四种亚型（A1A、A2A、A2B 和 A3AR），它们都是 G 蛋白偶联受体 (GPCR)，可以在基质细胞和上皮细胞上共表达 (10)。 CD73 也可以在效应 T 细胞上表达。包括 PC 在内的许多实体瘤的新数据表明，肿瘤上皮上过度表达的 CD73 会从 AMP 中产生细胞外腺苷，从而抑制 T 细胞和 NK 细胞的细胞毒性，从而促进肿瘤生长和疾病进展。 CD73 在 PC 生长中的重要性是众所周知的。 CD73 的这些免疫抑制和肿瘤促进功能使其成为预防和治疗胰腺癌的有吸引力的靶点。有多项临床试验测试了 CD73 靶向药物，包括小分子 CD73 抑制剂和抗 CD73 单克隆抗体，其原理是抑制 CD73 活性可能会增强 T 细胞和腺苷调节的其他免疫细胞水平的抗肿瘤免疫监视，从而延缓 PC 的发展。该项目的总体目标是评估临床相关小分子 CD73 抑制剂在胰腺癌同种移植物和重现人类胰腺癌进展的基因工程小鼠模型中的免疫预防作用。