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: 10451453
• 负责人: POWEL BROWN
• 金额: $ 80.25万
• 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 2023-12-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10451453
• 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; Financial Hardship; G-Protein-Coupled Receptors; Genes; Genetically Engineered Mouse; Goals; Growth; Hidrocystoma; Human; Human Genetics; Hypoxia; Immune; Immunologic Surveillance; Immunoprevention; 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; Prognosis; 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; 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）是一种高度侵略性的癌症，通常在晚期阶段被诊断出，并且任何癌症的进展最差。仅在2020年，仅在美国，就有将近57,600个人被诊断出患有PC，预计约47,050人死亡。尽管PC仅占美国所有癌症的3％，但约占所有癌症死亡的7％。此外，最近的事件和死亡率表明PC的趋势增加了。缺乏有效的早期干预措施是导致PC患者预后不良和衰退生存率的主要因素。尽管人类胰腺癌的分子遗传学取得了许多进步，但靶向疗法尚未转化为改善总体生存率。最近的发展表明，炎性前体（例如胰腺上皮内肿瘤（PANINS），毛细血管内粘液性肿瘤（IPMN）和囊这瘤，在发展为侵入性PC之前，许多年缓慢发展。 Yachida等。据估计，从胰腺上皮细胞受到诊断时的致命打击之初，就有大约10年的机会窗口，可以探索以实施早期干预策略。因此，制定预防癌症的预防和拦截策略，例如免疫预防，延迟/抑制/防止侵入前病变形成和/或进展到PC是最重要的，就像成功一样，它为增加生存而增强了生存的潜力，可以增强潜力。腺苷信号通路，特别是在增加细胞外腺苷的情况下，是肿瘤进展的重要驱动力。腺苷信号传导是一种细胞来减少炎症和低氧环境中感染的机制。 5'-核苷酸酶，也称为Ecto-5'-核苷酸酶或CD73，一种由NT5E基因编码的人类中的酶将细胞外腺苷单磷酸腺苷（AMP）转化为免疫抑制性腺苷，从而将抗抑制剂免疫抑制。通过腺苷受体的腺苷信号促进免疫抑制。有四种亚型的腺苷受体（A1a，A2a，A2b和A3AR），所有这些都是G蛋白偶联受体（GPCR），并且可以在基质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在内的许多实体瘤中的新兴数据表明，在肿瘤上皮上过表达的CD73从AMP中产生细胞外腺苷，这抑制了T细胞和NK细胞细胞毒性，从而抑制了肿瘤的生长和疾病进展。 CD73在PC增长中的重要性已建立。这些免疫抑制和肿瘤促进CD73的功能使其成为预防和治疗胰腺癌的目标。有几项临床试验测试CD73靶向剂，包括小分子CD73抑制剂和抗CD73单克隆抗体，基于抑制CD73活性的基本原理可以增强在T型和其他受adenosine pc necting PC开发的PCENDING PCENDING PCENDING PC开发的抗肿瘤免疫维持性的抗肿瘤免疫维持性。该项目的总体目的是评估胰腺癌临床相关的小分子CD73抑制剂的免疫预防作用，以及概括人胰腺癌进展的基因工程小鼠模型。