Redundant angiogenic signaling and tumor drug resistance

Angiogenesis research in the past two decades has contributed significantly towards understanding the molecular pathophysiology of cancer progression and inspired target-oriented research and pharma industry for the development of novel anti-angiogenic agents. Currently, over eleven drugs targeting angiogenesis have been approved by the FDA for the treatment of various malignancies. Of the registered anti-angiogenic clinical trials until the end of 2017 (ClinicalTrials.gov), over 47% were completed, 10% were terminated, 3% withdrawn, over 0.5% were suspended and only 4 trials have culminated in FDA approval for marketing. On the one hand, the clinical benefits of anti-angiogenic drugs prompted the development of novel anti-angiogenic agents. On the other hand, however, a plethora of recent studies demonstrated the emergence of tumor drug resistance towards currently used anti-angiogenic therapeutics. Series of preclinical and clinical studies have highlighted the enigma of drug resistance with functional bypass pathways, and identified compensatory or alternative angiogenic mechanisms assuring tumor growth in the midst of an anti-angiogenic stress environment. In the present review the classical literature of such redundant angiogenic pathways in concert with the key angiogenic factors and specialized cells involved in anti-angiogenic escape mechanisms is described. A strategic discourse regarding increasing tumor drug resistance and future modalities for anti-angiogenic therapy is also discussed in view of recent advances.