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

胰腺癌(PC)是一种高度侵袭性的癌症，通常在晚期确诊，是所有癌症中预后最差的。2020年，仅在美国，就将有近57600人被诊断出患有PC，预计将有约47050人死亡。尽管PC仅占美国所有癌症的3%左右，但它却占了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有增加的趋势。缺乏有效的早期干预是导致PC患者预后差、存活率低的主要原因。尽管在人类胰腺癌的分子遗传学方面取得了许多进展，但靶向治疗尚未转化为提高总体生存率。最近的研究表明，胰腺上皮内瘤变(Panins)、乳头内黏液瘤(IPMns)和囊腺瘤等侵袭性前体在发展为侵袭性PC之前进展缓慢。Ychida等人。已经估计，从胰腺上皮细胞受到致癌打击到确诊有大约10年的机会之窗，可以利用这一机会来实施早期干预策略。因此，发展癌症预防和拦截策略，如免疫预防，延缓/抑制/防止侵袭前病变的形成和/或进展到PC是至关重要的，因为如果成功，它将为提高存活率和减轻社会经济负担提供巨大的潜力。腺苷信号通路，特别是在细胞外腺苷增加的背景下，是肿瘤进展的重要驱动因素。腺苷信号是细胞在炎症和低氧环境中用来减轻炎症的一种机制。5‘-核苷酸酶，也被称为ecto-5’-核苷酸酶或CD73，是一种由NT5E基因编码的酶，在人类中将细胞外的腺苷(AMP)转化为免疫抑制腺苷，从而关闭抗肿瘤免疫监视。腺苷信号通过腺苷受体促进免疫抑制。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)，可在基质细胞和上皮细胞上共表达(10)。CD73也可在效应性T细胞上表达。在包括PC在内的许多实体肿瘤中出现的数据表明，在肿瘤上皮细胞过度表达的CD73会从AMP产生胞外腺苷，从而抑制T细胞和NK细胞的细胞毒作用，从而促进肿瘤的生长和疾病的进展。CD73在PC增长中的重要性已经得到了充分的证实。CD73的免疫抑制和促肿瘤作用使其成为预防和治疗胰腺癌的理想靶点。目前已有多项针对CD73靶向药物的临床试验，包括小分子CD73抑制剂和抗CD73单抗，其基本原理是抑制CD73活性可以在腺苷调节的T细胞和其他免疫细胞水平上增强抗肿瘤免疫监视，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基因工程小鼠模型中的免疫预防效果，该模型概括了人类胰腺癌的进展情况。

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.