Abstract 3924: Dual COX-2/sEH inhibition enhances immunotherapy and chemotherapy to induce bladder cancer regression
Authors: Vazquez Kimberly Lupita , Rothenberger Eva , Wang Weicang , Hwang Sung Hee , Bielenberg Diane R. , Hammock Bruce D. , Panigrahy Dipak 
Published: March 2024

Abstract
Unresolved inflammation plays a critical role in bladder cancer initiation and progression. Chemotherapy (e.g. gemcitabine and cisplatin), the standard of care for advanced bladder cancer, disrupts inflammation resolution and is only partially effective in preventing tumor recurrence after treatment. Immunotherapy has emerged as a potential treatment option for bladder cancer patients, however it is ineffective in 80% of patients and can induce a pro-inflammatory cytokine storm. Therefore, there is a critical unmet medical need to improve chemotherapy and immunotherapy in bladder cancer. To address this, we have developed dual COX-2/sEH inhibitors (e.g. PTUPB). This lead compound is representative of a newly patented class of “dual acting” molecules that target two important enzymes in the arachidonic acid cascade with nanomolar binding affinity: cyclooxygenase-2 (COX-2) and soluble epoxide hydrolase (sEH). Oral dosing of PTUPB is well-tolerated in animal models. Since chemotherapy and immunotherapy both induce tumor-promoting inflammation via an eicosanoid/cytokine storm, we hypothesized that dual COX-2/sEH inhibition would enhance immunotherapy in experimental bladder cancer via anti-inflammatory mechanisms. When syngeneic (MB49) bladder tumors reached ~200 mm3 in immunocompetent mice, treatment was initiated with PTUPB, anti-CTLA-4, anti-PD1, gemcitabine & cisplatin, or various combinations thereof. Here we demonstrate that chemotherapy and/or immunotherapy stimulated sEH and COX-2 expression in tumor tissue which was counter-regulated by PTUPB. While monotherapy treatment with PTUPB, gemcitabine & cisplatin, anti-PD1 or anti-CTLA-4 suppressed tumor growth compared to control, the tumors escaped single treatments by the end of the study. Remarkably, dual COX-2/sEH inhibition in combination with chemotherapy (gemcitabine and cisplatin) and/or immune checkpoint blockade (anti-CTLA-4 or anti-PD1) induced sustained tumor regression via synergistic anti-tumor activities. Chemotherapy and/or immunotherapy induced the expression of ER stress response genes (e.g. BiP and CHOP) and angiogenic factors (e.g. EGF and VEGF-C) in bladder cancer tissue, which were repressed by PTUPB. PTUPB also prevented chemotherapy-induced toxicity and prolonged survival in an orthotopic MB49 tumor model. Taken together, our results demonstrate dual COX-2/sEH inhibition as a novel therapeutic approach to enhance immunotherapy in bladder cancer without overt toxicity.
Citation Format: Kimberly Lupita Vazquez, Eva Rothenberger, Weicang Wang, Sung Hee Hwang, Diane R. Bielenberg, Bruce D. Hammock, Dipak Panigrahy. Dual COX-2/sEH inhibition enhances immunotherapy and chemotherapy to induce bladder cancer regression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3924.