Abstract 754: Targeting carbonic anhydrase IX in multiple pancreatic ductal adenocarcinoma models results in tumor growth inhibition and increased survival

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by aggressive growth, metastatic spread and poor 5 year survival rates of less than 5%. PDAC tumors develop extensive regions of hypoxia that contribute to its aggressive behavior and pose a significant hurdle to therapeutic response. Hypoxia-mediated adaptive responses for tumor cell survival and metastasis include metabolic reprogramming and pH regulation. Carbonic anhydrase IX (CAIX) is a membrane-bound, hypoxia-inducible enzyme that is highly expressed in solid tumors and functions as a critical component of the pH regulatory machinery required by hypoxic cancer cells for survival and metastasis. We have recently developed and validated novel small molecule inhibitors of CAIX and have demonstrated that these inhibitors are effective at reducing breast tumor growth and metastasis. The lead compound, SLC-0111, is currently being assessed in a Phase 1 clinical trial (NCT02215850). In the present study, we have evaluated the efficacy of targeting CAIX in PDAC using genetic and pharmacologic strategies. CAIX expression was found to be induced by hypoxia in a panel of human PDAC cell lines and was also upregulated in cell line-derived xenografts, patient-derived xenografts as well as the KRASG12D/p53-/- KPCY transgenic mouse model of PDAC (Rhim, AD et al. Cell, 2012:148;349-361). shRNA-mediated silencing of CAIX expression in PK-8 PDAC cells significantly reduced hypoxia-mediated cell proliferation (P<0.05) and invasion (P<0.01) in vitro, and dramatically delayed tumor growth (P<0.001) in vivo, resulting in increased median survival of the mice from 36 days to 59 days (P<0.01), similar to that observed following treatment with gemcitabine (36 days to 58 days, P<0.01). Interestingly, gemcitabine treatment in this model increased the fraction of CAIX-positive tumor cells, and silencing of CAIX expression in combination with gemcitabine treatment further delayed tumor growth (P<0.01) and increased median survival to 86 days (P<0.01). Similarly, sequential administration of gemcitabine and the CAIX inhibitor, SLC-0111, significantly delayed tumor growth (P<0.01) and enhanced survival (P<0.01) in PK-8 and PK-1 xenografts, compared to gemcitabine alone. Preliminary data indicate that treatment with SLC-0111, alone and in combination with gemcitabine inhibits the growth of spontaneous PDAC tumors in the KPCY transgenic model of PDAC, as assessed by ultrasound imaging. These results demonstrate that CAIX plays an important role in PDAC progression and is a potential therapeutic target for pancreatic cancer. A focused Phase 1b clinical trial of gemcitabine and SLC-0111 in patients with metastatic PDAC is planned, based on the outcome of the Phase 1 trial. Citation Format: Paul C. McDonald, Shawn C. Chafe, Marylou Vallejo, David Schaeffer, Don Yapp, Claudiu T. Supuran, Ben Stanger, Mac Parmar, Daniel Renouf, Shoukat Dedhar. Targeting carbonic anhydrase IX in multiple pancreatic ductal adenocarcinoma models results in tumor growth inhibition and increased survival. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 754.