Normalizing Tumor Vasculature Using Sepiapterin to Increase Radiosensitivity

Our studies examine the role of nitric oxide synthase (NOS) in tumor vasculature. NOS is “uncoupled” in tumor cells, resulting in peroxynitrite (ONOO-) formation in lieu of nitric oxide (NO). NO signaling is critical for vascular function, thus uncoupling of eNOS in endothelial cells may partly explain the poor vasculature found within tumors. NOS can be “recoupled” through Sepiapterin (SP) treatment of tumor cells. We examined whether SP could normalize tumor vasculature, promoting radiosensitivity. Optoacoustic tomography of flank xenografts and spontaneous tumor models demonstrate that SP significantly enhances percent oxyhemoglobin in tumors. Immunohistochemical analysis of SP-treated tumors showed significant reduction in CD31 staining and significant increases in smooth muscle actin (SMA), both hallmarks of vascular normalization. SP resulted in over a two-fold increase in apoptosis with irradiation. These data demonstrate potential for SP as an adjuvant in cancer treatment. Future studies will examine drug uptake and mechanisms behind vascular normalization