Abstract B141: Repurposing of ketorolac for the treatment of renal cell carcinoma (RCC)

Abstract

Abstract Renal cell carcinoma (RCC) is the most common type of kidney cancer, accounting for more than 90% of malignant kidney tumors. The incidence of RCC in the eight major markets will increase by 63% over the forecast period of 2013 to 2023 (1). The currently available treatment options include antiangiogenic agents and tyrosine kinase inhibitors (TKIs), while immunotherapies are under development. The 5-year survival rate is approximately 90% (2); however, the 5-year overall survival for patients with distant metastatic RCC is only 12% (2). Thus, despite advances in the treatment of RCC, the prognosis for patients remains poor when the disease has metastasized beyond the kidneys (3), signifying a clear unmet medical need for new treatment options, particularly for high-risk stage II and III RCC patients undergoing surgery. Repurposing existing drugs is an attractive alternative as conventional drug discovery is expensive and time-consuming. In addition, preclinical and clinical data are widely available for such drugs, in turn reducing the time and resources required to bring a candidate drug to clinical trial. Using this strategy we have established the ability of ketorolac as a potential anticancer agent against RCC. Ketorolac is a nonsteroidal anti-inflammatory drug currently indicated for the short-term management of moderately severe acute pain, usually in a postoperative setting. We have tested the in vitro antiproliferative activity of Ketorolac in a panel of ten human RCC cell lines in 2D and 3D models. Ketorolac showed average IC50 value of 3.75 mM and 2.08 mM in the 2D and 3D models respectively. Interestingly, however, the combination of ketorolac with sunitinib, a standard-of-care, showed additive to synergistic effect as seen using the Bliss independence index. The data show that in RXF 1183L cells the combination shows additive effect while synergistic effect was seen in A-498 cells at 125 µM to 500 µM of ketorolac and 0.625 µM to 2.5 µM of sunitinib. Further, we validated the in vitro combination data by performing in vivo efficacy study in athymic nude mice. Ketorolac at 5 mg/kg p.o. and 10 mg/kg p.o. and sunitinib at 20 mg/kg p.o. inhibited tumor formation by up to 51%, 73%, and 50%, respectively. A combination of ketorolac at 5 mg/kg p.o. and 10 mg/kg p.o. with sSunitinib at 20 mg/kg p.o. inhibited tumor formation by 81% and 85%, respectively, clearly indicating superior antitumor efficacy as compared to drug alone. While understanding the mechanism of action (MOA) of ketorolac we astoundingly invented a novel role for ketorolac as an inducer of prostate apoptosis response-4 (PAR-4), a proapoptotic tumor suppressor protein. This indicates the unique use of Ketorolac as a secretagogue causing release of PAR-4 from normal cells; further, this released PAR-4 can cause apoptosis specifically in cancer cells. We thus conclude that this remarkable efficacy can be attributed to the dual MOA of ketorolac as a COX inhibitor and PAR-4 inducer, making it an interesting candidate for repurposing against renal cell carcinoma. 1. PharmaPoint. Renal Cell Carcinoma - Global Drug Forecast and Market Analysis to 2023. 2. National Cancer Institute. SEER Stat Fact Sheets: Kidney and Renal Pelvis. Available from: http://seer.cancer.gov/statfacts/html/kidrp.html. Accessed February 2016. 3. Ljungberg B, Campbell S, Cho H. The epidemiology of renal cell carcinoma. Eur Urol. 2011;60:615-621. Citation Format: Jeevan Deepak Ghosalkar, Siddhika Rajiv Raut, Mariamma Charles Thekkumpurath, Geena Malhotra, Kalpana Sanjay Joshi. Repurposing of ketorolac for the treatment of renal cell carcinoma (RCC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B141.