Abstract 2013: A carbonic anhydrase inhibitor methazolamide potentiates efficacy of gemcitabine by modulating anti-proliferative activity and cancer stem cell markers in pancreatic carcinoma

Abstract

Abstract Pancreatic cancer is the fourth cause for cancer related deaths globally. By 2020, incidence of new cases is expected to be 420,000 with equal number of associated mortalities. Overall 5-year survival has marginally improved over past despite of our growing understanding of the disease. Surgery remains standard of care for resectable tumors followed by adjuvant chemotherapy which resulted in median survival of 26 months. Newer therapies targeting stroma and immunotherapies hold promise for the future. Noticeably, a high unmet medical need warrant novel therapy to extend survival over a year in metastatic settings. Drug repositioning holds promise over the conventional drug discovery, as it reduces development time and cost. Using this approach, we report promising anticancer activity of Methazolamide (MZM) in pancreatic cancer. MZM, a synthetic derivative of sulphonamide and a carbonic anhydrase IX (CA) inhibitor is used for the treatment of ocular conditions for lowering intraocular pressure. Overexpression of CA is implicated in acidification of tumor microenvironment leading to hypoxia which in turn promotes growth and metastasis of the tumor. Therefore, modulation of extracellular tumor pH via inhibition of CA represents a promising course to anticancer therapy. Here, we report anti-proliferative activity of MZM in 12 pancreatic cell lines including patient derived (PDX) in 2D models and anchorage independent growth inhibition in 3D models. Combination treatment with GEM yielded significant growth inhibition than drug alone in all tested cell lines. Additive effects were observed for the combination in PDX-1986, PDX-546, Capan-2, Mia-Pa-Ca and PANC-1 cells. Further, in vivo efficacy of MZM in combination with GEM was performed using PDX-546 in nude mice. Combination group showed significant tumor growth inhibition (72%, p<0.05) as against drug alone, MZM at 60 mg/kg, p.o. (50%, p<0.05) and GEM at 50 mg/kg i.v. (61%, p<0.05). There was no significant body weight loss. For PK/PD studies, MZM levels were measured in tumors and PD effect was evaluated using various markers in tumor samples. Expression of target genes was measured by qRT-PCR. Significant reduction in expression of stem cell markers viz. RAC1, OCT4, CD34, CD14, Nanog and proliferation marker (Ki67) was observed in combination group as compared to drug alone. In addition, anti-angiogenic potential viz. would healing, tube formation and expression of important anti-angiogenic markers like HIF1α, VEGF were profoundly modulated in MZM and combination group. Thus, our study indicates that the combination of MZM, a CA inhibitor with GEM is a promising novel approach for the treatment of pancreatic cancer especially in metastatic settings. Citation Format: Kalpana Joshi, Jeevan D. Ghosalkar, Vinay R. Sonawane, Siddhika R. Raut, Geena Malhotra. A carbonic anhydrase inhibitor methazolamide potentiates efficacy of gemcitabine by modulating anti-proliferative activity and cancer stem cell markers in pancreatic carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2013.