LAUSR

Neuroblastoma (NB) is the most common pediatric extracranial solid tumor. Based on tumor stage and histological features, 50% of NBs are classified as high-risk diseases, a subtype characterized by a quite unsatisfactory long-term survival even with the striking advances in NB management that have been achieved in the past decades. Cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) cascade has been reported to foster a proinflammatory tumor-nourishing microenvironment in NB. However, the specific downstream PGE2 receptor (EP) subtype which directly mediates this tumor promoting effect remains elusive. Therefore, in our research, we aim to 1) elucidate the culprit EP receptor that is directly involved in NB development; 2) evaluate the feasibility of inhibiting the PGE2 receptor subtype as a novel treatment strategy for high-risk NB. To start with, we analyzed the gene expression profiles of the COX2/PGE2/EP pathway from four major NB datasets (Versteeg, Kocak, SEQC, and NRC) on R2 platform. It indicates that the COX-2/PGE2/EP2 signaling axis is highly associated with the expression of high-risk NB markers, as well as an abysmal overall survival rate. Moreover, a time resolved fluorescence resonance energy transfer (TR-FRET) method was adopted to reveal that EP2 receptor is the key Gαs-coupled receptor that mediates PGE2-initiated cAMP signaling in high-risk NB cell lines. Genetic interference of EP2 receptor expression by CRISPR/Cas9-mediated genome editing and doxycycline induced conditional knockdown significantly inhibited high-risk NB development and progression both in neuro-sphere formation assay and in nude mice xenograft models. Finally, we tested the anti-NB efficacy of our recently developed selective and bioavailable small-molecule EP2 antagonists. With a consecutive treatment of three weeks, decreased tumor size and weight have been observed in both high-risk NB xenograft model and immunocompetent allograft model, simultaneously with decreased inflammation, angiogenesis, and enhanced apoptosis. Collectively, our results suggest that the PGE2/EP2 pathway contributes to the growth and malignant potential of high-risk NB; pharmacological inhibition on EP2 receptor by our drug-like compounds might provide a novel therapeutic strategy for this deadly pediatric cancer. Citation Format: Ruida Hou, Ying Yu, Jun Yang, Jianxiong Jiang. Prostaglandin E2 receptor EP2: A novel target for high-risk neuroblastoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4923.