K. Takabe1, E. Katsuta1, M. Nagahashi2 1Roswell Park Cancer Institute,Breast Surgery, Department Of Surgical Oncology,Buffalo, NY, USA 2Niigata University Graduate School Of Medical And Dental Sciences,Division Of Digestive And General Surgery,Niigata, , Japan
Introduction: Obesity is one of the most prevalent health issues in the US. It has been shown that obesity-related breast cancer is more aggressive with poor prognosis, which is partly explained by the low-grade inflammation caused by obesity. Recently we have published that sphingosine-1-phosphate (S1P), a signaling lipid mediator, link inflammation and cancer in colitis-associated colon cancer. FTY720, a functional antagonist of S1P signaling, is an immune-modulator that dramatically reduces peripheral lymphocyte counts and other inflammatory cells. We hypothesized that addition of FTY720 thus suppress the effect of obesity-mediated inflammation should enhance anti-cancer effect of doxorubicin, which is one of the most commonly used anti-cancer drug for breast cancer as part of the standard of care.
Methods: Female B6.cg-Lepob (ob/ob) mice fed with high fat diet for 2 weeks prior to implantation of 1×106 murine mammary adenocarcinoma E0771 cells into #2 right fat pads as previously described (Katsuta et al JSR 2016), were used as an obesity model, and litter mate control mice fed with normal diet were used as a control. Both ob/ob and control mice were randomized into 4 groups in each group; vehicle, Doxorubicin, FTY720 and Combination of Doxorubicin and FTY720. Doxorubicin was administrated 5 mg/kg on Day 0 and 3 i.p. FTY720 was administered 1 mg/kg daily p.o. during the entire course. Tumor growths were measured daily by caliper measurements. Tumor weights were measured on 21 days after cell inoculation.
Results: The body weight of obesity model was significantly heavier than control mice at the time of cancer cell inoculation (44.1 g vs 19.4 g; p < 0.001). In non-treatment group, tumor weight in obesity group was significantly heavier than control mice (1232 mg vs 966 mg; p = 0.049), which is consistent with the dogma that obesity worsen cancer progression. As expected, tumor weight in non-treatment group was heavier than any treatment group, and that in combination treatment of doxorubicin and FTY720 was lightest in both of obesity group and control group. Interestingly, tumor reduction rate in obesity group compared with non-treatment group is significantly greater than control group (Doxorubicin: 83% vs 19%, p=0.001; FTY720: 80% vs 46%, p=0.027, Doxorubicin + FTY720: 93% vs 64%, p=0.011). Over 15% weight loss were seen in obesity doxorubicin group and obesity combination treatment group.
Conclusion: Immune-modulator FTY720 enhanced the efficacy of doxorubicin particularly in obese mice, which implicate a novel approach to treat obesity-associated breast cancer.