Abstract 2610: Targeting the mTOR pathway for the prevention of ER-negative breast cancer

Abstract

Abstract Background: Prevention of estrogen receptor (ER)-positive breast cancer prevention is now possible antiestrogen drugs; however, this treatment is ineffective against ER-negative breast cancers. ER-negative breast cancer occurs more often in younger women and is associated with a poor prognosis. Dysregulation of PI3K-mTOR pathway, specifically upregulation of mTOR and loss of phosphatase and tensin homolog (PTEN) has been commonly associated with ER-negative breast cancers and been shown to be associated with poor prognosis. We hypothesized that by targeting mTOR, will suppress the growth of ER-negative and triple negative breast cancers. To test the hypothesis, we used MMTV-erbB2, C3(1)/SV40T, and p53 null mammary gland mouse models to determine whether mTOR inhibitor everolimus is effective in preventing growth of ER-negative mammary tumors. Methods p53-null Balb/C donor mice were transplanted into both cleared inguinal mammary fat pads of Balb/C p53 wild-type mice. All mice were separated into 2 groups 1) sesame oil control and 2) everolimus (5 mg/kg). All treatments were given by oral gavage, five days a week from 3 months of age for MMTV-erbB2 and 2 months of age for SV40T mice, and in case of p53 mice, two months after transplantation. Mice were observed daily for tumor formation, toxicity and the percentage of tumor free mice were recorded. Tumor incidence and time to tumor formation was visualized using Kaplan Meier curves and analyzed using the generalized Wilcoxon test. Results: In MMTV-erbB2 mice the mTOR inhibitor, everolimus reduced tumor incidence and was associated with an increase in median survival time from 240 days to 410 days in. At 365 days, when all mice in control group died, only half of the mice treated with everolimus had developed mammary tumors. Long term treatment of everolimus was associated with mild toxicity that includes weight loss (<10%) and skin changes (matted hair, skin erythema). Everolimus also reduced tumor incidence in C3 (1)/SV40 mice, with an increase in median survival time from 130 days to median survival which has not reached yet (>180 days). At 150 days, when all mice from the control group developed tumor only 35% mice from treatment group had developed tumors. Everolimus also significantly reduced tumor incidence in p53 null mammary gland mice. At 420 days, when approximately in 50% of the control mice developed mammary tumors compare to only 7% of the everolimus treated mice developed tumors. Conclusion: The mTOR inhibitor everolimus prevented ER-negative mammary in two mouse models (MMTV-erbB2, C3 (1)/SV40, and p53 null mammary gland mice). Based on our results Everolimus is an effective cancer preventive drug. Our results suggest that, studies with reduced everolimus dose alone or in combination with other targeted therapies such as selective estrogen receptor modulators are warranted. In the future, clinical trials of the everolimus should be considered for the prevention of breast cancer in high-risk patients. Citation Format: Abhijit Mazumdar, Yun Zhang, Jamal Hill, Powel Brown. Targeting the mTOR pathway for the prevention of ER-negative breast cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2610.