Abstract 2230: Combined treatment with agonists for CXCR4 and CB2 receptors reduces prostate cancer growth and metastasis.

Abstract CXCR4 is a G-protein-coupled receptor (GPCR) widely expressed in tumors, regulates cell migration, survival, and immune responses through activation by stromal cell-derived factor-1α (SDF-1α), contributing critically to metastasis and tumor aggressiveness. Our previous in vitro studies demonstrated that CXCR4 forms heterodimers with the cannabinoid receptor 2 (CB2) in human breast and prostate cancer cell lines. Simultaneous stimulation of CXCR4 and CB2 with SDF-1α and the CB2 agonist AM1241 induced the formation of a physical dimer, which markedly suppressed CXCR4-mediated pro-tumorigenic signaling, reduced cell migration, disrupted cytoskeletal organization, and downregulated motility-associated proteins. Given the reported anti-metastatic effects of cannabinoids and the results of our heterodimer, we hypothesized that simultaneous activation of CXCR4 and CB2 could attenuate tumor progression in vivo. To test this, we established a spontaneous metastasis model using luciferase-expressing human prostate cancer cells (DU145 RFP/Luc or PC3 GFP/Luc) implanted subcutaneously into male NSG mice. Once tumors reached ∼40 mm3, mice were randomized into four treatment groups: vehicle, SDF-1α, AM1241, or simultaneous SDF-1α+ AM1241. Primary tumors were surgically resected at ∼400 mm3, and treatments continued post-resection to assess metastasis and recurrence. Mice that received the combined agonist treatment exhibited no local tumor recurrence, a significant reduction in tumor volume, and a markedly lower incidence of distant metastases compared to all other groups. These findings demonstrate that concurrent CXCR4 and CB2 activation inhibits tumor growth and dissemination, as we observed in vitro, suggesting that targeting the CXCR4-CB2 receptor complex represents a promising alternative to traditional CXCR4 antagonists for managing metastatic prostate cancer. Citation Format: Nakea Michelle Pennant, Alifiani Bonita Hartono, Shiqin Liu, Sidharth Paparaju, Chung Lee, Christopher Massey, Tanya Ivanova Stoyanova, Cimona V. Hinton. Combined treatment with agonists for CXCR4 and CB2 receptors reduces prostate cancer growth and metastasis abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2230.