Abstract 659: Inhibiting autophagy improves the efficacy of VN/12-1 over all-trans retinoic acid in a HER2 over-expressing SK-BR3 breast cancer xenograft model

Purpose: Autophagy is a critical physiological process of cell survival in the presence of stress and is an important cause of resistance to anti-cancer therapy. Drugs that inhibit autophagy (e.g. chloroquine) deprive the cells of this protective mechanism and therefore are promising agents in a combination therapy of breast cancer. Our group has designed and synthesized a novel retinoic acid derivative, VN/12-1. We reported previously that VN/12-1 is a potent inducer of autophagy in estrogen independent, HER2 over-expressing breast cancer cell line SK-BR3 in vitro. In the present study, we used chloroquine in combination with VN/12-1 in an SK-BR3 xenograft model to test the hypothesis that the combination of VN/12-1 and chloroquine would result in greater efficacy against SK-BR3 tumors compared to VN/12-1 alone or all-trans retinoic acid (ATRA) alone. Experimental Design: To test this hypothesis, 64 female SCID mice (8 mice per group) were inoculated with SK-BR3 cells. Once the tumors formed, the mice were treated with vehicle (control), VN/12-1 and ATRA alone or in combination with chloroquine for 30 days. The two dosages of VN/12-1 for the groups involving VN/12-1 were 2.5 mg/kg and 5 mg/kg. The doses of ATRA and chloroquine were 5 mg/kg and 50 mg/kg, respectively. All the agents were administered subcutaneously (s.c) twice a week. Results: Out of all the treatment groups, both the dosages of VN/12-1 (2.5 mg/kg and 5mg/kg) when used in combination with chloroquine were the most effective in inhibiting the growth of SK-BR3 tumors (70% and 80% growth inhibition respectively compared to vehicle control). The combination of ATRA with chloroquine did not show statistically significant inhibition of tumor growth. The effect of each treatment on the body weight and the weights of uteri was also determined. No toxicities were observed as noted by no significant changes in the weight of the mice. The data about the tumor samples’ analysis for the effect of each treatment on the expression of various tumor markers and autophagy markers and pharmacokinetic studies on VN/12-1 will be presented. Conclusion: Our studies have demonstrated for the first time that the combination of VN/12-1 and chloroquine can be used to treat estrogen independent breast cancer. It is hoped that this combination therapy would solve the problem of the development of acquired resistance due to autophagy that typically follows therapeutic treatment of breast cancer. We envision further advanced preclinical development of this combination therapy as potential therapy for breast cancer. 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 659. doi:10.1158/1538-7445.AM2011-659