Targeting Angiogenic Factors Contributing to Etiology and Progression of Human Ovarian Cancer

Abstract

Abstract : Development of human ovarian cancer depends, in part, on formation of an adequate blood supply. Tumor angiogenesis is essential for cancer growth, and vascular endothelial growth factor (VEGF) is important in stimulating growth of vascular endothelial cells. VEGF is produced by many ovarian cancers, and our data show that VEGF secretion is markedly up-regulated in ovarian cancers with HER-2 gene overexpression. Herceptin, an antibody to HER-2 receptor, has direct antitumor effects, but the antireceptor antibody also elicits a significant reduction in VEGF secretion from ovarian cancer cells, and, thereby, also retards ovarian tumor- associated angiogenesis. More complete suppression of angiogenesis can be elicited by treatments that suppress blood vessel proliferation, such as squalamine, an angiostatic steroid recently approved by the FDA as an orphan drug candidate for the treatment of ovarian cancer. In studies with ovarian cancer cells in vivo, squalamine elicits antitumor activity by suppressing the angiogenic action of several vascular growth factors including VEGF. This ongoing work evaluates the efficacy of squalamine alone and combined with other antitumor therapies, including cisplatin and Herceptin, in suppressing the growth of ovarian cancers with and without HER-2 gene overexpression.