KSEF R&D Excellence: A Novel Natural Product Inhibitor for Inflammatory Angiogenesis

(i). Specific Aims Aim 1. To test our hypothesis that WA targets the ubiquitin-proteasome pathway (UPP) We will investigate the 20S proteasome as a mediator of WA's inhibitory activity on endothelial cell cycle and NF-KB activation. As an alternate site of WA's activity on the UPP, we will investigate the inhibitory activity of WA on ubiquitin isopeptidase, also a potential target that is rationalized by our preliminary findings. Aim 2. To elucidate the molecular basis ofWA's inhibitory activity on angiogenesis We will first investigate the efficacy of WA as an inhibitor of angiogenesis in the C57BLl6J mouse strain, for which the corneal inflammatory model of neovascularization will be employed. Using this model, we will next investigate whether SJLlJ mice, a strain known to be resistant to anti-angiogenic clinical drugs like TNP-470 (cell cycle inhibitor) and thalidomide (NF-KB inhibitor), is sensitive to WA because of WA's upstream potent UPP-targeting activity. We plan to validate this hypothesis by assessing WA's activity on the 20S proteasome, ubiquitin isopeptidase and candidate downstream targets of the UPP, in vascularized healing corneal tissues from WA-treated SJLlJ and C57BLl6J mice. (ii). Background and Significance Anti-angiogenesis was proposed by Dr. Judah Folkman in the early 1970s as a therapeutic strategy to blunt tumor growth by targeting the destruction of the pathological capillaries that nourish cancers (4).This strategy has recently been validated in the clinic with the demonstration that Avastatin [anti-vascular endothelial growth factor (VEGF) antibody] treatment prolongs the lives of patients with advanced colon cancer (5).While there is sound scientific and clinical rationale for pursuing angiogenesis inhibitors for cancer treatment in humans, it is also becoming apparent that anti-angiogenic agents alone are not expected to treat all cancers (or other non-oncological angiogenesis-dependent diseases) equally, as clinically evidenced from the poor outcome for advanced breast cancer patients treated with the anti-VEGF antibody (6). 3