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

• 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
• 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

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.

项目摘要/摘要 胰腺导管腺癌（PDA）是一种致命的恶性肿瘤 肿瘤微环境有助于肿瘤生长并抑制药物递送。生存率差，苛刻 疾病的治疗和肿瘤固有方面，例如疼痛和细胞因子池的改变，促进高 PDA患者的焦虑程度。将近25％的胰腺癌患者处方苯二氮卓类药物处方 （BZD）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在修饰肿瘤微环境中的作用尚不清楚。最近的 研究表明，N-取代的BZD促进了质子感应G蛋白偶联的信号传导 受体，GPR68，在酸性条件下，例如PDA肿瘤微环境中存在的受体。 GPR68 PDA癌症相关的成纤维细胞（CAF）过表达，其表达驱动脱木质，纤维化， 以及炎症，与药物输送和化学抗性受损相关的微环境特征。 为了建立临床相关性，对胰腺癌患者进行了协变量调整后的分析 从2004年到2020年，在罗斯威尔公园接受了化学疗法。 GPR68激活剂相对于非用户，无进展生存率（PFS）显着降低（HR 3.83 （1.53,9.57）），而GPR68非激活剂接受Alprazolam（ALP）的患者显着改善了PFS （HR 0.38（0.16-0.92））。使用源自KPC小鼠的皮下同种异体移植的初步研究，这是一种遗传学 PDA的工程鼠标模型表明LOR促进了胶原蛋白沉积，脱木质和缺血性 在体内坏死，支持该BZD可能促进不利的肿瘤微环境 负面影响PDA患者的生存。此外，经过洛尔处理的CAF的表达增加了 炎症和促纤维化基因，表明CAF可能正在推动观察到的表型。 这些发现导致了一个中心假设，即GPR68激活BZDS调节CAF信号，这一点 会增加脱木质，随后收缩肿瘤脉管系统。长期目标是 确定BZD对PDA肿瘤微环境和化学治疗功效的影响。这 假设将以两个目标进行检验。 AIM 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，含有肿瘤的KPC小鼠中的脱木质。 AIM 2将评估 BZD在修改CAF信号传导和活动中的作用。促纤维蛋白的表达/分泌变化， BZD处理的永生CAF的炎症细胞因子和GPR68下游信号分子将是 量化。 BZD处理的CAF的PDA器官增殖和胶原蛋白收缩的改变也将是 量化。这项研究具有临床意义，因为它将表明BZD是否通常为PDA处方 患者以可能降低化学治疗功效的方式修饰PDA肿瘤微环境。