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

摘要

Development of 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 critical to stimulate growth of vascular endothelial cells. VEGF is produced by ovarian cancers, with secretion markedly increased in ovarian cancers with HER-2 oncogene overexpression. Herceptin antibody to HER-2 receptor has direct antitumor effects, but the antibody also reduces VEGF secretion from ovarian cancers, and, thereby, retards ovarian tumor-associated angiogenesis. More complete blockade of angiogenesis may be elicited by treatments that synergistically suppress blood vessel proliferation, such as squalamine, an angiostatic steroid approved by the FDA as an orphan drug candidate for treatment of ovarian cancer. In studies with ovarian cancer cells in vivo, squalamine elicits' antitumor activity by suppressing angiogenuc actions of several vascular growth factors including VEGF, an effect due to squalamine binding in caveolae, with downstream blockade of p44/p42 and p38 MAP kinases. Squalamine also shows antitumor efficacy when combined with other therapies, including cisplatin, carboplatin and Herceptin, and is a good candidate for further assessment in clinical trials among patients afflicted with ovarian cancer.