Abstract
Epithelial ovarian cancer (EOC) is the most frequent cause of death from all gynecological malignancies with the majority of women being diagnosed with advanced stage disease. It is considered a chemosensitive cancer with a high initial response rate to first-line platinum and taxane-based chemotherapy. However, a majority of patients will relapse with subsequent resistance to treatment and ultimately succumb to their disease. This emphasizes the need for the development of new therapeutic approaches to improve outcomes.
Angiogenesis has been recognized as an important mechanism promoting EOC growth and metastasis with angiogenesis inhibitors being developed and tested for over a decade. Bevacizumab, a humanized monoclonal antibody, that targets vascular endothelial growth factor A (VEGF-A), has been the most well evaluated molecular targeted drug in the treatment of advanced and recurrent EOC with proven clinical efficacy. However, anti-VEGF therapies are often associated with serious toxicities and drug resistance ultimately develops. Hence, new therapeutic approaches are needed.
Targeting the angiopoietin-Tie-2 complex pathway (VEGF independent) has gained interest over the last few years as an alternative strategy to overcome anti-VEGF therapy resistance and toxicity. Trebananib (formerly known as AMG 386; Amgen, Thousand Oaks, CA, USA) is a novel first-inclass angiopoietin antagonist, which inhibits angiopoietin-1 and angiopoietin-2 interaction with the Tie-2 tyrosine kinase receptor and hence, disrupts tumor angiogenesis.
In preclinical models trebananib has shown antiangiogenesis and antitumor activity. It also has shown antitumor activity as a monotherapy with an acceptable toxicity profile in recurrent EOC. It prolonged progression-free survival in a recently published randomized Phase III clinical trial in the recurrent setting (TRINOVA-1). However, overall survival was unchanged.
Keywords: AMG 386, angiogenesis, angiopoietin, ovarian cancer, trebananib, targeted therapy, VEGF.
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