Abstract 1558: STX140 but not paclitaxel inhibits mammary tumor initiation, progression and metastasis in C3(1)/SV40 T/t-antigen transgenic mice

Abstract

Abstract New chemotherapeutic options for late-stage metastatic breast cancer are urgently required. Currently, the taxanes are considered one of the most effective treatments for late-stage cancer treatment. Paclitaxel and the novel cytotoxic agent STX140, compounds that have shown significant activity against numerous xenograft mouse models of cancers, are here investigated in the C3(1)/SV40 T/t-antigen mouse model of spontaneous breast cancer. This mouse model recapitulates important histopathological and molecular alterations in mammary cancer development over a highly predictable time-course. At 8 weeks of age, the female animals develop low-grade mammary intra-epithelial neoplasia (MIN) lesions. By 12 to 14 weeks of age this progresses to high-grade MIN, which is similar to human ductal carcinoma in situ. From 15 weeks of age onwards invasive, metastatic carcinomas are observed. STX140 and paclitaxel were administered to these mice at 12 weeks of age (early intervention) and when tumors had reached 0.5 cm (late intervention). Results demonstrated that all mice in the control and paclitaxel treated groups at early intervention developed palpable mammary cancer which grew to 3112 mm3 by 25 weeks of age and led to the termination of these animals at week at this time point. However, STX140, when administered at week 12 onwards, blocked disease progression and no palpable tumor develop in 47% of tumors and significantly inhibited the growth of tumors that did develop. This resulted in a significant (P < 0.01) survival advantage for animals treated with STX140. Conversely, in C3(1)/SV40 mice, paclitaxel failed to inhibit tumor growth and therefore did not confer a survival benefit. In the late treatment groups, STX140 significantly (P < 0.05) inhibited primary mammary cancer growth and also resulted in a significant (P < 0.001) survival advantage compared to control animals. Furthermore, it was observed that paclitaxel treatment increased liver metastases in these mice. To conclude, STX140 has a greater anti-cancer efficacy and conferred an improved survival outcome compared to paclitaxel in a clinically relevant transgenic mouse model of metastatic breast cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1558.