Targeting the A2B Adenosine Receptor for Immunoprevention of Pancreatic Cancer

靶向 A2B 腺苷受体用于胰腺癌的免疫预防

基本信息

批准号：
10929664
负责人：
Xiangwei Wu
金额：
$ 59.36万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-03-14
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10929664
关键词：
ADORA3 gene Adenosine Adenosine A2B Receptor Adenosine Monophosphate Benchmarking Cancer Center Cell Line Data Development Diagnosis Drug Kinetics Epithelial Cells Excision Future Genetically Engineered Mouse Goals Human Immune system Immunoprevention Immunosuppression Intervention Isogeneic graft Laboratories Lesion Malignant Neoplasms Malignant neoplasm of pancreas Mediator Modeling Operative Surgical Procedures Pancreatic Ductal Adenocarcinoma Pancreatic Intraepithelial Neoplasia Pathway interactions Patients Pharmacodynamics Preventive Clinical Trial Prognosis Purinergic P1 Receptors Signal Pathway Signal Transduction Stromal Cells Testing Therapeutic Toxic effect Treatment Protocols clinically relevant efficacy evaluation high risk population immunoregulation in vivo inhibitor mouse model optimal treatments pharmacokinetics and pharmacodynamics premalignant receptor screening subcutaneous tumor tumor microenvironment

项目摘要

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.

腺苷信号通路已成为肿瘤微环境的重要介体。在该途径中，通过CD73活性将腺苷一磷酸（AMP）转化为腺苷，在胰腺上皮内肿瘤（PANIN）中升高，导致腺苷在前癌的微环境中积累（1-6）。通过腺苷受体促进微环境中免疫抑制的腺苷信号（7-9）。有4个腺苷受体（A1A，A2A，A2B和A3AR）可以在基质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中高度表达的受体，也可以预测预后不良（11）。这些数据表明，腺苷A2B受体的存在在临床上是相关的。 PDAC患者对腺苷途径进行了几项持续的努力。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）中的药代动力学和功效，这些模型（GEMMS）概括了人类Panin启动并发展为先进的Panin。从该项目获得的数据对于PDAC高风险人群的预防临床试验的未来开发至关重要，例如在MD Anderson癌症中心之后。