Abstract 1654: Evaluation of combination of low doses of chemotherapy and anti-stathmin therapy in mammary tumors

Abstract

Abstract AIM: Stathmin, a founding member of a family of microtubule-destabilizing proteins, is expressed at high levels in breast cancer (BC) and provides an attractive target for BC therapy. We previously showed that stathmin inhibition could suppress the malignant phenotype of BC cells in vitro and in vivo. Here, we tested whether the therapeutic efficacy of stathmin inhibition could be further enhanced by combining it with standard chemotherapeutic agents in vivo. METHODS: We used a bicistronic adenoviral (Ad) vector that coexpresses green fluorescent protein (GFP) and a ribozyme (Rz) that targets human stathmin mRNA. Thirty-five female nude mice were injected orthotopically in the mammary fat pad of two of the mammary glands (# 4), each with 5×10e6 MDA-MB-231 cells/gland. We initiated treatment after the mice developed tumors of 0.3-0.4 cm in size. Mice bearing established MDA-MB-231 xenografts were divided into 7 groups of 5 mice each. Group I was injected with PBS alone. Groups 2, 3 & 4 were injected with control Ad.GFP (1×10e8 vp/injection). At the same time, adriamycin (5 mg/kg/injection) & taxol (5 mg/kg/injection) was co-administered in groups 3 & 4 respectively. Similarly groups 5, 6 & 7 were injected with Ad.Rz.GFP (1×10e8 vp/injection) anti-stathmin adenovirus. Groups 6 & 7 were also given adriamycin & taxol respectively at the same doses. The adenovirus & the drugs were administered at subtherapeutic doses that were selected based on dose response experiments. All drugs were injected i.p. & the adenoviruses were injected intratumorally once a week for a total of 3 injections. Changes in tumor growth were monitored in the different groups for another 6-8 weeks. RESULTS: Tumors in animals injected with PBS (group 1) or the control Ad.GFP (group 2) continued to grow to larger sizes. The growth of the tumors in animals treated with low doses of drugs alone (groups 3 & 4) or Ad.Rz.GFP alone (group 5) was only modestly slowed compared to control groups. When animals were treated with a combination of low doses of anti-stathmin therapy & adriamycin (group 6), the rate of tumor growth was much slower than animals treated with drug alone or anti-stathmin Rz alone. Interestingly, when animals were treated with a combination of low doses of anti-stathmin therapy & taxol (group 7), tumor regression (greater than or equal to 40%) was observed in 60% of the tumors & 40% of the tumors were stabilized. Although inhibition of tumor growth was observed in both the combination treatment groups compared to groups treated with single agent alone, combination of anti-stathmin therapy & taxol had a more profound inhibition of tumorigenicity, since both agents target the same microtubule pathway. In contrast, the activity of adriamycin does not result from direct interactions with microtubules & the mitotic spindle. These findings are highly relevant for the treatment of BC, since taxol is one of the most active chemotherapeutic agents used in BC care. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1654. doi:10.1158/1538-7445.AM2011-1654