Ovarian cancer is among the most devastating of gynecological cancers primarily impacting postmenopausal women. Induction of angiogenesis, the process of generating and remodeling blood vessels, is a critical requirement for tumor growth and metastasis in multiple cancers including ovarian, leading to the use anti- angiogenic agents in the clinic. However side effects and toxicities can limit their use. Thus there remains a need to identify cancer specific, safe ways to control angiogenesis in ovarian cancer. Inhibin is a unique TGF-? family member whose levels are extremely low in normal post-menopausal women. However Inhibin is an established biomarker for ovarian cancers with unknown functions. Our preliminary studies show that Inhibin expression is regulated by hypoxia, a well-appreciated regulator of tumor angiogenesis. We find that Inhibin exhibits paracrine effects on the endothelium by increasing angiogenesis in vitro and in vivo. Mechanistically, Inhibin requires the endothelial specific receptors Endoglin and Alk1 to induce angiogenesis. Since Inhibin is expressed in ovarian cancers, but present at low systemic levels in normal post-menopausal women we will examine Inhibin as a potential novel angiogenic target for cancer the mechanism of action. The hypothesis to be tested is that blocking tumoral Inhibin, a novel ligand for endothelial specific TGF-? receptors, and a product of the hypoxia adaptive response that promotes angiogenesis will result in suppression of tumor angiogenesis.
The specific aims are: 1) To test if blocking Inhibin has therapeutic anti-angiogenic effects in ovarian cancer alone or in combination with current anti-angiogenic therapies. 2) To delineate the mechanism of Inhibin induced endothelial cell remodeling and angiogenesis using a combination of cell signaling, biochemical and biophysical approaches to test Inhibin as a direct novel ligand for endothelial receptors endoglin and Alk1 and identify novel signaling targets of Inhibin using transcriptomics. 3) To define hypoxia mechanisms regulating Inhibin expression. I believe that these investigations into Inhibin-mediated angiogenesis will provide the first insights into previously unknown functions for Inhibin that is broadly expressed in cancer and provide new targets to safely treat angiogenesis in cancer.
Inhibin is an established diagnostic marker for ovarian cancers. The goal is to define Inhibin as a therapeutic target and gain new knowledge about Inhibin's mechanism of action by using a comprehensive therapeutic and mechanistic strategy . Successful completion of these studies will improve our ability to control and manage ovarian cancer.