Impact of benzodiazepines on the pancreatic tumor microenvironment

苯二氮卓类药物对胰腺肿瘤微环境的影响

基本信息

批准号：
10541834
负责人：
Abigail Carissa Cornwell
金额：
$ 2.14万
依托单位：
ROSWELL PARK CANCER INSTITUTE CORP
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2023-08-18
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10541834
关键词：
Address Adverse effects Allografting Alprazolam Anti-Anxiety Agents Anxiety Automobile Driving Benzodiazepines Blood Vessels Chemoresistance Clinical Collagen Deposition Desmoplastic Development Disease Drug Delivery Systems Fibroblasts Fibrosis G-Protein-Coupled Receptors GPR68 gene Genes Genetically Engineered Mouse Goals Growth Histologic Human Image Impairment Inflammation Inflammatory Ischemia KRASG12D Lorazepam Malignant Neoplasms Malignant neoplasm of pancreas Methods Modeling Mus Nausea Necrosis Organoids Outcome Pain Pancreatic Ductal Adenocarcinoma Patient-Focused Outcomes Patients Perfusion Pharmaceutical Preparations Phenotype Progression-Free Survivals Proliferating Proteins Protons Recommendation Research Role Signal Transduction Signaling Molecule Sleeplessness Survival Rate Testing Treatment Efficacy Treatment Protocols Work cancer risk chemotherapy clinically relevant clinically significant constriction cytokine epidemiology study improved in vitro activity in vivo mouse model overexpression pancreatic cancer patients pancreatic ductal adenocarcinoma model pancreatic neoplasm subcutaneous treatment response tumor tumor growth tumor microenvironment

项目摘要

PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDA), is a lethal malignancy, due in part to a dense, desmoplastic (fibrotic) tumor microenvironment which aids tumor growth and inhibits drug delivery. Poor survival rates, harsh treatments, and tumor intrinsic aspects of the disease such as pain and altered cytokine pools, promote high levels of anxiety in PDA patients. Nearly 25% of pancreatic cancer patients are prescribed benzodiazepines (BZDs) to treat anxiety, insomnia, or to relieve nausea. Epidemiological studies indicate that BZDs may increase the risk of cancer development but the role of BZDs in modifying the tumor microenvironment is unknown. Recent studies indicate that n-unsubstituted BZDs promote the signaling of the proton-sensing G protein-coupled receptor, GPR68, under acidic conditions, such as those present in the PDA tumor microenvironment. GPR68 is overexpressed by PDA cancer-associated fibroblasts (CAFs), and its expression drives desmoplasia, fibrosis, and inflammation, microenvironmental features associated with impaired drug delivery and chemoresistance. To establish clinical relevance, covariate adjusted analyses was conducted of pancreatic cancer patients who received chemotherapy at Roswell Park from 2004 to 2020. Patients receiving lorazepam (LOR), a strong GPR68 activator, had significantly decreased progression-free survival (PFS) relative to non-users (HR 3.83 (1.53,9.57)), while patients receiving alprazolam (ALP), a GPR68 non-activator, had significantly improved PFS (HR 0.38 (0.16-0.92)). Preliminary studies using subcutaneous allografts derived from KPC mice, a genetically engineered mouse model of PDA, indicated that LOR promoted collagen deposition, desmoplasia, and ischemic necrosis in vivo, supporting that this BZD may promote an unfavorable tumor microenvironment that could negatively impact PDA patient survival. Additionally, LOR-treated CAFs had increased expression of pro- inflammatory and pro-fibrotic genes, suggesting that CAFs may be driving the observed phenotype. These findings led to the central hypothesis that GPR68-activating BZDs modulate CAF signaling, which will increase desmoplasia, subsequently constricting the tumor vasculature. The long-term goal is to determine the impact of BZDs on the PDA tumor microenvironment and chemotherapeutic efficacy. This hypothesis will be tested with two aims. Aim 1 will determine the impact of LOR/ALP on the PDA vasculature and desmoplasia in tumor-bearing KPC mice, using imaging and histological methods. Aim 2 will evaluate the role of BZDs in modifying CAF signaling and activity. Changes in the expression/secretion of pro-fibrotic proteins, inflammatory cytokines, and GPR68 downstream signaling molecules by BZD-treated immortalized CAFs will be quantified. Alterations in PDA organoid proliferation and collagen contraction by BZD-treated CAFs will also be quantified. This research is clinically significant because it will indicate if BZDs commonly prescribed to PDA patients modify the PDA tumor microenvironment in a manner which may decrease chemotherapeutic efficacy.

项目概要/摘要胰腺导管腺癌 (PDA) 是一种致命的恶性肿瘤，部分原因是致密、促纤维化（纤维化）肿瘤微环境有助于肿瘤生长并抑制药物输送。成活率低，环境恶劣治疗以及疾病的肿瘤内在方面（例如疼痛和改变的细胞因子池）促进高 PDA 患者的焦虑水平。近 25% 的胰腺癌患者服用苯二氮卓类药物（BZD）用于治疗焦虑、失眠或缓解恶心。流行病学研究表明 BZD 可能会增加癌症发展的风险，但 BZD 在改变肿瘤微环境中的作用尚不清楚。最近的研究表明，n-未取代的 BZD 可以促进质子感应 G 蛋白偶联的信号传导受体，GPR68，在酸性条件下，例如存在于 PDA 肿瘤微环境中的条件。探地雷达68 PDA 癌症相关成纤维细胞 (CAF) 过度表达，其表达会导致结缔组织增生、纤维化、以及炎症、与药物输送受损和化疗耐药相关的微环境特征。为了建立临床相关性，对以下胰腺癌患者进行了协变量调整分析： 2004 年至 2020 年在罗斯威尔公园接受化疗。接受劳拉西泮 (LOR) 的患者，这是一种强效药物相对于未使用 GPR68 激活剂的患者，无进展生存期 (PFS) 显着降低（HR 3.83） (1.53,9.57))，而接受阿普唑仑 (ALP)（一种 GPR68 非激活剂）的患者的 PFS 显着改善（HR 0.38（0.16-0.92））。使用源自 KPC 小鼠皮下同种异体移植物的初步研究，KPC 小鼠是一种基因 PDA 工程小鼠模型表明，LOR 促进胶原蛋白沉积、结缔组织增生和缺血体内坏死，支持这种 BZD 可能促进不利的肿瘤微环境，从而可能对 PDA 患者的生存产生负面影响。此外，经 LOR 处理的 CAF 的 pro-表达增加。炎症和促纤维化基因，表明 CAF 可能驱动观察到的表型。这些发现得出了一个中心假设：激活 GPR68 的 BZD 可以调节 CAF 信号传导，从而将增加结缔组织增生，随后收缩肿瘤脉管系统。长期目标是确定 BZD 对 PDA 肿瘤微环境和化疗效果的影响。这假设将通过两个目标进行检验。目标 1 将确定 LOR/ALP 对 PDA 脉管系统的影响使用成像和组织学方法，对荷瘤 KPC 小鼠进行结缔组织增生。目标 2 将评估 BZD 在改变 CAF 信号传导和活性中的作用。促纤维化蛋白表达/分泌的变化， BZD 处理的永生化 CAF 产生的炎症细胞因子和 GPR68 下游信号分子将被量化。 BZD 处理的 CAF 也会改变 PDA 类器官增殖和胶原收缩。量化。这项研究具有临床意义，因为它将表明 BZD 是否常用于 PDA 患者以可能降低化疗效果的方式改变PDA肿瘤微环境。