Abstract 4498: Assessing the effects of the small molecule cathepsin L inhibitor, KGP94: combination with radiotherapy and evaluation of antimetastatic potential in vivo

Abstract

Abstract Introduction: KGP94, a small molecule cathepsin L inhibitor, has previously been shown to effect growth delay in a C3H mammary carcinoma model, while in vitro experiments suggest it may have anti-metastatic potential. The aim of this study was to investigate the anti-tumoral effects of KGP94 in the C3H mammary carcinoma when combined with radiotherapy, and to investigate the effects on metastasis in the murine SCCVII carcinoma model. 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 by dissolving in a mixture of 10% Tween 80 and 90% HEPES-buffer. KGP94 was intraperitoneally injected at 0.01ml/g mouse bodyweight. When C3H mammary carcinomas reached a volume of 200 cubic mm, the non-anaesthetised mice were restrained and tumors locally irradiated (230 kV x-rays) with a single dose of 10 Gy. KGP94 (20 mg/kg) was intraperitoneally injected either before (immediately, 2 days, or 4 days) or after (immediately, 2 days, or 4 days) irradiation. Anti-tumor activity was assessed by determining the tumor growth time, which was either the time in days to reach 3 times the volume (TGT3) at irradiation or the time in days to reach a volume of 500 cubic mm (TGT-500) from tumor initiation. For the metastases study, SCCVII tumor material was inoculated on day 0. On day 5 KGP94 treatment was started (10mg/kg) and continued for a further 10 days. Mice were then euthanized and their lungs were removed and put in Bouin's solution overnight. Lung metastases could easily be visualized and were counted manually. 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: For established C3H mammary carcinomas, the TGT3 for control animals was 4.2 days and for the KGP94 treated animals 5.8 days. The TGT3 for radiation alone was 12 days and the various combinations with KGP94 resulted in TGT3s ranging from 10.5 to 12.5 days. For initiation studies the TGT-500 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 tumours with 10 mg/kg KGP94 for 5 days from the day of initiation significantly increased the TGT-500 for both tumour models to around 21 and 17 days respectively. The metastasis study revealed that 5 out of 10 mice in the control group developed lung metastasis, whereas only 3 out of 10 mice did so in the KGP94 treated group. Conclusion: KGP94 has a small effect on established tumors when given alone, but did not enhance the response to radiation therapy. However, KGP94 significantly delayed the initial growth of primary tumors, suggesting an effect on metastasis that was confirmed in the lung metastasis studies. Citation Format: Thomas R. Wittenborn, Michael R. Horsman. Assessing the effects of the small molecule cathepsin L inhibitor, KGP94: combination with radiotherapy and evaluation of antimetastatic potential in vivo. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4498. doi:10.1158/1538-7445.AM2015-4498