Discovery and Development of Antiangiogenetic Drugs in Ovarian Cancer

It is more than 30 years since the seminal observations by Folkman of the development of new blood vessels (angiogenesis) in tumors. Ovarian cancer remains the most lethal gynecologic malignancy in the US, and angiogenesis is a particularly important target as VEGF levels are high, manifest as ascites and pleural effusions, and the response rates to single agent bevacizumab, a recombinant humanized monoclonal antibody directed against VEGF, are the highest (16-25%) of any reported in oncology. Antiangiogenics have generally been well tolerated, but are associated with gastrointestinal perforation in 1-2%. New angiogenesis targets are being identified (ANG-2, PDGFR, FGFR, inflammation and the microenvironment), and a plethora of new agents is in clinical development: tyrosine-kinase inhibitors (sunitinib, cediranib, pazopanib), multitargeted agents (XL-184), anti-angiopoietins (trebananib), novel antivascular approaches (VB-111 and ombrabulin). Antiangiogenic therapy appears to impact PFS, but does not impact cure. In subsets of patients, it may improve overall survival (OS), and its use remains costly and controversial. Although approved in Europe, the pathway to approval of bevacizumab for ovarian cancer in the US is currently still unclear. There is a clinical need to define the role of these drugs in ovarian cancer management and to identify robust predictive biomarkers.

Keywords: Aflibercept, angiogenesis, bevacizumab, blood, cediranib, disruption, dormancy, endothelium, factor, inhibitor, kinase, maintenance, normalization, novel, pazopanib, progression, remission, survival, trebananib, tyrosine, vascular, vessel.