The Preclinical Development of FTY720, A Sphingosine-1-Phosphate Receptor Modulator, as a Novel Targeting Therapy Against Breast Cancer

Abstract

Introduction: Sphingosine-1-phosphate (S1P), is a bioactive lipid mediator and a ligand for five specific G-protein coupled receptors (S1P1-5), that regulates critical processes of cancer progression, such as cell proliferation, migration, and angiogenesis. As such, this molecule is expected to provide a good target against breast cancer. FTY720, a sphingosine analogue that antagonize the S1P1 receptor, is currently in clinical use for multiple sclerosis with FDA approval. Phase 3 clinical trials of FTY720 for the transplant population dosed the drug at 5mg po daily (equivalent to 0.8mg/kg po daily for mice) for up to 2 years with minimal side effects. Previously, FTY720 has been shown to inhibit breast cancer growth in a mouse model which required a notably higher dose (over 2mg/kg ip daily) above any other used in clinical trials. Thus, FTY720 has not been developed as an anti-cancer drug to date. Recently it has been shown that oral administration is more potent than intraperitoneal injection of FTY720. the purpose of this study was to evaluate the efficacy of FTY720 against breast cancer in an acceptable dosing under an appropriate route of administration, using oral instead of intaperitoneal injections. Methods: We used a syngeneic model with orthotopically implanted 4T1-luc2 murine breast cancer cells, which best mimics human breast cancer progression.FTY720 was then administered orally in either 1, 0.5 or 0.3mg/kg daily dosing. the overall tumor burden was quantified using bioluminescence technology over 19 days, and tumor weights were measured at the nineteenth day. Pathological analysis was performed to determine the anti-cancer effect of FTY720. Results: Overall tumor burden increased exponentially after 4T1-luc2 cell implantation, where lymph node metastases were confirmed from day 2, and lung metastasis from day 8 by bioluminescence. the groups treated with 1mg/kg and 0.5mg/kg FTY720 showed significantly reduced tumor burden compared with the control group and the 0.3mg/kg FTY720 group. at time of sacrifice, the tumor weights in the control groups were significantly heavier than in those groups treated with either the 1mg/kg or 0.5mg/kg FTY720 (p=0.005, p<0.001 respectively). the 0.3mg/kg FTY720 group, on the other hand, showed no difference in tumor weight or overall tumor burden compared with control group. Conclusions: They key role of S1P in breast cancer progression suggests that FTY720 would be an effective treatment against this disease. Previous studies required the dose of the drug in levels far exceeding tolerable dose for humans. in our study, we demonstrated that lower doses of FTY720 to 0.5mg/kg in mouse, which is equivalent to 3mg in human, are effective in inhibiting breast cancer progression when administered orally.