Abstract 1816: Assessment of anti-tumor activity of the cathepsin L inhibitor, KGP94

Abstract

Abstract Purpose: The cysteine cathepsin proteases are known to play an important role in tumor progression, invasion and angiogenesis. The present study evaluated the anti-tumor activity and pharmacokinetics of the small-molecule cathepsin L inhibitor KGP94. Materials and Methods: Male CDF1 or C3H/HeNHsd mice were inoculated on the right rear foot with a C3H mammary carcinoma or a SCCVII carcinoma, respectively. A solution of KGP94 was prepared each day by dissolving in a mixture of 10% Tween 80 and 90% HEPES-buffer. It was intraperitoneally injected at 0.01 ml/g mouse bodyweight. Various doses (1-20 mg/kg) were administered between 1-20 days, starting from the day of tumor inoculation. Anti-tumor activity was assessed by determining the tumor growth time, which was the time in days to reach a volume of 500 mm3 (TGT500). Pharmacokinetics of KGP94 were investigated by drawing blood samples before, and up to 24 hours after KGP94 injection. Results are listed as Mean (± Standard Error). One-way ANOVA comparison of group means was performed, and a P<0.05 was considered significant. Results: The TGT500 for control animals was 18.0 days (± 0.3) for the C3H mammary carcinoma and 13.6 days (± 0.7) for the SCCVII carcinoma. Treating tumors with KGP94 significantly increased the TGT500 for both tumor models to around 21 and 17 days respectively, when doses were at 10.0 mg/kg or higher. At a dose of 5.0 mg/kg the TGT500 of the C3H mammary carcinoma was significantly increased to 21.4 days (± 1.1), whereas the TGT500 of the SCCVII carcinoma was unchanged at 13.8 (± 0.2). At lower KGP94 doses neither tumor model showed significant growth delay. Additional experiments with the C3H mammary carcinoma model showed that treatment was most effective when started immediately after tumor inoculation, and that treatment for 5 days was just as effective as 20 days. Pharmacokinetic analysis of KGP94 levels in mouse plasma is ongoing. Conclusion: In the C3H mammary carcinoma KGP94 significantly delayed tumor growth, but the effect was primarily on the early phase following tumor cell inoculation. This suggests that KGP94 may have a more significant role in inhibiting the establishment of metastasis rather than influencing the growth of established tumors. Significant growth delay was also observed in the SCCVII tumor model. However, it occurred with higher doses of KGP94 compared to the C3H mammary carcinoma. The higher dose could be explained by the more aggressive nature of the SCCVII tumor model. Supported by The Danish Cancer Society, The Danish Council for Independent Research: Medical Sciences, and OXiGENE Inc. Citation Format: Thomas R. Wittenborn, Michael Stratford, Mary Lynn Trawick, Kevin G. Pinney, David J. Chaplin, Dietmar W. Siemann, Michael R. Horsman. Assessment of anti-tumor activity of the cathepsin L inhibitor, KGP94. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1816. doi:10.1158/1538-7445.AM2014-1816