Celecoxib Fixed-Dose Combination: Antitumor Activity On Tumor Growth And Metastasis

Background: Breast cancer and melanoma are associated with a high rate of lymphatic and hematogenous metastasis which results in high rate of cancer mortality. Inflammation and hypertension (HTN) have recently emerged as causal factors for tumor progression and anti-hypertensive agents have been shown to reduce inflammation and suppress tumor growth and metastasis. Cyclooxygenase-2 (COX-2) is upregulated in most human tumors and is a potent inducer of cancer-associated inflammation that promotes tumor angiogenesis and lymphangiogenesis. This study evaluated a novel combination of a selective COX-2 inhibitor with three antihypertensive drugs to suppress tumor growth and metastasis in preclinical xenograft models. Methods: Three anti-hypertensive drugs were evaluated in this study: i) Lisinopril [LIS], an inhibitor of angiotensin-1 converting enzyme (ACE); ii) Olmesartan medoxomil (OLM), an angiotensin II receptor blocker (ARB); and iii) Hydrochlorothiazide (HCTZ), a thiazide diuretic along with Celecoxib [CEL], a selective COX-2 inhibitor. CEL, LIS, OLM, and HCTZ were evaluated either alone or in combination for tumor growth suppression and metastatic spread in an orthotopic xenograft model of triple-negative inflammatory breast cancer/SUM149 and subcutaneous xenograft models of melanoma/MDA-MB-435, glioblastoma/U87-MG, and triple-negative SUM159. Luciferase-tagged SUM149 and MDA-MB-435 cell lines were used to determine the incidence and the burden of locoregional and systemic spread. Mice were monitored twice a week for 9-16 weeks for percent weight loss, tumor volume and survival outcome. Metastatic tumor burden and incidence was measured as luciferase expression in lymph nodes and lungs and normalized to total protein. Results: In the SUM149 model, the saline treated control had an average tumor burden of 17.6 ± 8.6 x104 RLU per mg of protein in the ipsilateral lymph nodes (ILN). Two groups, OLM alone and CEL + OLM, had a statistically significant decrease in ILN burden. Olmesartan alone had a 7.1-fold decrease in tumor burden with an average of 2.4 ± 0.6 x104 RLU per mg of protein (p-value = 0.01 by Mann-Whitney test). Similar trend was observed for LIS, but not for HCTZ. In the subcutaneous model, synergistic antitumor activity was observed with OLM (p = 0.026) at low dose but not with LIS and CEL (p = ns). At high dose, LIS, OLM, and CEL showed significant inhibition of tumor growth but no synergy. When these agents were combined with Paclitaxel in the SUM159 model, there was only additive effect. HCTZ, an antihypertensive diuretic which has no direct impact on the vascular wall had no effect on tumor growth. Conclusion: These preclinical data strongly suggest a hitherto unappreciated role of ACE/ARB in tumor growth control and support the further exploration of fixed-dose combinations of CEL with ACE/ARB in cancer, especially inflammatory breast cancer. Citation Format: Cynthia Lee, Osmond J. D9Cruz, Kevin Ng, Vuong Trieu. Celecoxib fixed-dose combination: antitumor activity on tumor growth and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4902. doi:10.1158/1538-7445.AM2017-4902