Abstract PO-047: Lorazepam modifies the pancreatic ductal adenocarcinoma tumor microenvironment

Abstract

The aim of this work was to determine the role of the benzodiazepine (BZD) lorazepam, an anxiolytic drug, in modifying the pancreatic ductal adenocarcinoma (PDA) tumor microenvironment. PDA is a lethal malignancy. Poor survival rates and tumor intrinsic aspects of the disease, such as altered cytokine pools, promote significant levels of anxiety in patients. Approximately 25% of PDA patients will be prescribed BZDs. Epidemiological evidence suggests BZDs increase the risk of cancer development, but no group has determined the impact of BZDs on the PDA tumor microenvironment. Recent research has established that BZDs promote the signaling of GPR68, a proton-sensing G protein-coupled receptor activated by the acidic tumor microenvironment. GPR68 is expressed on PDA cancer-associated fibroblasts (CAFs) and promotes pro-inflammatory and pro-fibrotic signaling. Additionally, we performed covariate adjusted analyses of pancreatic cancer patients who received chemotherapy at Roswell Park from 2004 to 2020. Patients receiving lorazepam (LOR), an n-unsubstituted BZD that strongly activates GPR68, had shorter progression-free survival (PFS) relative to non-users (HR 3.83 (1.53, 9.57). In contrast, patients receiving alprazolam (ALP), an n-substituted BZD and GPR68 non-activator, had improved PFS relative to non-users (HR 0.38 (0.16-0.92). It is essential that we determine the impact of BZDs and GPR68 activation on the PDA tumor microenvironment and therapeutic response. We hypothesize that BZDs which are strong GPR68 activators will stimulate fibrosis and inflammatory signaling, promoting a more desmoplastic tumor microenvironment, decreasing the efficacy of chemotherapy. Using a subcutaneous KPC allograft mouse model, we found that lorazepam, a strong GPR68-activating BZD, modified the tumor microenvironment by increasing α-SMA (smooth muscle actin) expression, collagen deposition, and ischemic necrosis. Similarly, under acidic conditions, lorazepam-treated primary mouse and human CAFs promoted the mRNA expression of α-SMA and the pro-inflammatory cytokine, interleukin-6. Overall, this research indicates that lorazepam treatment significantly impacts the PDA tumor microenvironment. Significance: This research may guide the development of new clinical recommendations for prescribing anxiolytic drugs to PDA patients. The results of this research will likely be applicable to other cancer types which are reliant on CAFs for growth, such as colon cancer. Citation Format: Abigail C. Cornwell, Abdulrahman A. Alahmari, Arwen A. Tisdale, Michael E. Feigin. Lorazepam modifies the pancreatic ductal adenocarcinoma tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-047.