Abstract 3383: Tumor vasculature normalization by recoupling nitric oxide synthase with a tetrahydrobiopterin precursor

Abstract

Abstract The abnormal, irregular nature of tumor vasculature has been well documented. The aberrant nature of the vasculature results in uneven, heterogeneous blood flow and leaky, hemorrhagic blood vessels. Due to the unusual nature of tumor vessels, areas of hypoxia tend to develop that contribute to radioresistance and inefficiency of therapeutic drug delivery. Our current studies examine the role of nitric oxide synthase (NOS) in tumor vasculature. NOS has been demonstrated to be “uncoupled” in tumor cells due to reduced levels of tetrahydrobiopterin (BH4), a necessary cofactor, resulting in peroxynitrite (ONOO-) formation in lieu of nitric oxide (NO). NO signaling is critical for vascular function and thus uncoupling of eNOS in the endothelial cells may partly explain the poor vasculature structure found within solid tumors. Having previously demonstrated that NOS can be “recoupled” and NO production restored through treatment of tumor cells with Sepiapterin (SP), a BH4 precursor, we examined whether SP could normalize tumor vasculature, promoting radiosensitivity and improving drug uptake. Multispectral optoacoustic tomography analysis of both flank tumor xenografts and a spontaneous breast tumor model (MMTV) demonstrate that SP given orally significantly enhances the percent of oxyhemoglobin in the tumor. Immunohistochemical analysis of tumors treated with SP showed a significant reduction in CD31 staining and a significant increase in smooth muscle actin (SMA), both hallmarks of vascular normalization. Ex vivo analysis of tumors revealed that the enhanced tumor oxygenation resulted in over a two-fold increase in radiation induced cell killing. These preliminary data demonstrate great potential for SP as an adjuvant in the treatment of cancer, especially when we take into consideration that SP has been demonstrated to be cytotoxic to both breast and colon tumors. Future studies will examine drug uptake in tumors as well as the mechanism behind the vascular normalization. Citation Format: Christopher Rabender, Ninu Bruno, Ross B. Mikkelsen. Tumor vasculature normalization by recoupling nitric oxide synthase with a tetrahydrobiopterin precursor. [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 3383.