Targeting the A2B Adenosine Receptor for Immunoprevention of Pancreatic Cancer

腺苷信号通路已成为肿瘤微环境的重要介质。在该途径中，一磷酸腺苷（AMP）通过CD 73活性转化为腺苷，其在胰腺上皮内瘤变（PanIN）中升高，导致腺苷在癌前微环境中积累（1-6）。腺苷信号通过腺苷受体促进微环境中的免疫抑制（7-9）。有4种腺苷受体（A1 A、A2 A、A2 B和A3 AR）可在基质和上皮细胞上共表达（10）。在腺苷受体中，A2 B受体是唯一一种在PanIN和PDAC中高度表达的受体，也是预后不良的预测因子（11）。这些数据表明腺苷A2 B受体的存在具有临床意义。有几个正在进行的努力，靶向腺苷途径治疗PDAC患者。本项目的总体目标是评价A2 B抑制剂在遗传工程小鼠（GEM）模型（GEMM）中的药代动力学和疗效，该模型重现了人PanIN启动和进展为晚期PanIN。从该项目中获得的数据对于未来在PDAC高危人群中开展预防性临床试验至关重要，例如MD安德森癌症中心进行的预防性临床试验。

The adenosine signaling pathway has emerged as an important mediator of the tumor microenvironment. In this pathway, adenosine monophosphate (AMP) is converted to adenosine through CD73 activity, which is elevated in pancreatic intraepithelial neoplasia (PanIN), causing accumulation of adenosine in the precancerous microenvironment (1-6). Adenosine signals via adenosine receptors promoting immune suppression in the microenvironment (7-9). There are 4 adenosine receptors (A1A, A2A, A2B and A3AR) which can be co-expressed on stromal and epithelial cells (10). Among the adenosine receptors, the A2B receptor is the only one highly expressed in PanINs and PDAC and is also predictive of poor prognosis (11). These data suggest that the presence of the adenosine A2B receptor is clinically relevant. There are several ongoing efforts targeting the adenosine pathway therapeutically in PDAC patients. The overall goal of this project is to evaluate the pharmacokinetics and efficacy of A2B inhibitors in genetically engineered mouse (GEM) models (GEMMs) that recapitulate human PanIN initiation and progression to advanced PanIN. The data obtained from this project would be essential for the future development of a preventive clinical trial in a PDAC high risk population, such as the one followed at MD Anderson Cancer Center.