Combining SecinH3 with Spingolipids to Target Triple-Negative Breast Cancer

Cancer cells require continuous access to nutrients due to mutations that constantly drive biosynthetic pathways. 4f2hc is a chaperone protein that is required for the surface expression amino acid transporters that provide nutrients to the cell. FTY720 is a soluble, orally bioavailable FDA-approved drug for multiple sclerosis. At higher doses than are required for immunosuppression, FTY720 induces cell death in cell several cancer cell lines. Our lab has shown that FTY720 down-regulates transporters for amino acids and glucose (Romero Rosales et. al., 2011). In vivo, FTY720 selectively kills cancer cells without major impact on non-transformed cells. FTY720’s ability to reduce nutrient uptake makes it a possible therapy that would be very effective towards triple-negative breast cancer (TNBC). Most of the current breast cancer therapies target either HER-positive cells, or progesterone and estrogen receptors. Since TNBCs do not over-express HER2 or progesterone or estrogen receptors, there are no current therapies that are effective against TNBCs (Crown J, O'Shaughnessy et al. 2012). However, TNBC cells rapidly accumulate radioactive glucose and are detectable by FDG-PET imaging. Thus, a metabolic therapy such as FTY720 could be highly effective against TNBCs (Pierobon M, Frankenfeld 2013). Like all cancer cells, TNBC cells also have constitutively active anabolism and therefore are sensitized to nutrient stress. Preliminary experiments from our lab show that with the Arf6 inhibitor SecinH3 potentiates FTY720-induced cell death in MBA-MB-231 cells (a TNBC cell line). Because FTY720 has a dose-limiting toxicity, our lab has developed an analog of FTY720 that could be safely used in patients, SH-BC-893. Whether SecinH3 can potentiate SH-BC-893-induced cell death in TNBC models 4T1 and MDA-MB-231 cells will be tested in vitro and in vivo if results are promising. Cell proliferation and viability will be measured separately by flow cytometry. This technique avoids the caveats of other cell death assays that measure cellular metabolic activity rather than whether cells are dead or alive. SH-BC-893 IC50 curves will be generated in the presence and absence of SecinH3. I hypothesize that SecinH3 will potentiate cell death and reduce proliferation in combination with the FTY720 analog. If so, SH-BC-893 may be more effective as an antitumor agent when used in combination with SecinH3.