Targeting the A2B Adenosine Receptor for Immunoprevention of Pancreatic Cancer

腺苷信号通路是肿瘤微环境的重要调节因子。在这一途径中，腺苷一磷酸(AMP)通过CD73活性转化为腺苷，在胰腺上皮内瘤变(Panin)中升高，导致腺苷在癌前微环境中积聚(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(A1a、A2a、A2b和A3AR)可在基质细胞和上皮细胞上共表达(10)。在腺苷受体中，A2B受体是唯一在Panins和PDAC中高表达的受体，也预示着不良预后(11)。这些数据表明，腺苷A2B受体的存在与临床相关。有几项针对PDAC患者的腺苷途径的治疗正在进行中。该项目的总体目标是评估A2B抑制剂在基因工程小鼠(GEM)模型(GEMM)中的药代动力学和疗效，该模型概括了人类Panin的启动和进展到晚期Panin。从该项目中获得的数据将对未来在PDAC高危人群中开展预防性临床试验至关重要，例如在MD Anderson癌症中心进行的试验。

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.