Blocking Tumoral Angiogenesis VEGF/VEGFR Pathway: Bevacizumab-20 Years of Therapeutic Success and Controversy

Abstract

The "angiogenesis switch"-defined as the active process by which solid tumors develop their own circulation-plays an important role in both tumoral growth and propagation. As the malignant tumor grows and reaches a critical size, the metabolic needs as a function of an ever-increasing distance to the nearest emergent blood vessel, can no longer be covered by the microenvironment of the peritumoral tissue. Although a relatively discrete process, the "angiogenic switch" acts as a limiting stage of tumoral development present from the avascular hyperplasia phase to the vascularized neoplastic phase, providing support for tumor expansion and metastasis. Over time, research has focused on blocking the angiogenetic pathways (such as VEGF/VEGFR signaling axis) leading to the development of targeted therapeutic agents such as Bevacizumab. Objectives: We conducted a review of the molecular principles of tumoral angiogenesis and we tried to follow the history of Bevacizumab from its first approval for human usage 20 years ago to current days, focusing on the impact this agent had in solid tumor therapy. A comprehensive review of clinical trials pertaining to Bevacizumab (from the era of the preclinic trials leading to approval for human usage, to the more recent randomized trial focusing on combination targeted therapy) further details the role of this drug. We aimed to establish if this ancient drug continues to have a place in modern oncology. Conclusions: Bevacizumab, one of the first drugs targeting tumoral microenvironment, remains one of the most important oncologic agents blocking the VEGF/VEGFR angiogenic pathway. otherwise, history of 20 years marked by numerous controversies (ranging from methodological errors of clinical trials to withdrawal of approval for human usage in breast cancer patients, from discussions about severe side effects to resistance to therapy and limited efficacity), Bevacizumab continues to provide an optimal therapeutic option for many solid tumors that previously had little to no means of treatment, improving otherwise bleak outcomes. Even in the era of personalized precision oncology, Bevacizumab continues to be a key element in many therapeutic regimens both as monotherapy and in combination with newer targeted agents.

Keywords: Bevacizumab; VEGF; VEGF receptors; angiogenesis; angiogenesis inhibitors; molecular mechanisms; resistance to antiangiogenetic drugs.

Figure 1

The mechanism of pathological tumoral angiogenesis. PHD—prolyl hydroxylase—an enzyme that under normal oxygenation conditions causes the hydroxylation of the alpha subunit of HIF-1 resulting in its inactivation. HIF1alpha and HIF1beta—the alpha and beta subunits of HIF-1. EC—endothelial cells. VEGF—vascular endothelial growth factor. EGF—epithelial growth factor. FGF—fibroblast growth factor. TNF-alpha—tumor necrosis factor alpha. PDGF—Platelet-derived growth factor. VEGFR—receptor for VEGF. EGFR—EGF receptor. FGFR—FGF receptor. Tie, Met—tyrosine-kinase receptors with a role in tumor proliferation. TAM—tumor associated macrophage. Treg—T cells with regulatory role. Tie2 Mo—monocytes expressing the Tie2 receptor for angiopoietin. References pertaining to the making of the figure above: [1,2,3,4,16,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35].

Figure 2

VEGF-dependent intracellular mechanisms involved in angiogenesis. VEGF (vascular endothelial growth factor); VEGFR2 (VEGF receptor 2); Grb2 (Growth factor receptor-bound protein 2)—is an adapter protein involved in signal transduction and cellular communication; Sos-1 (son of sevenless-1)—regulatory protein (activator) of Ras proteins by promoting the transformation of GDP (guanosine-diphosphate) into GTP (guanosine-triphosphate); GAP—GTP-ase-activating protein; Raf (Raf protein kinase)—key intermediary role between membrane GTPases and downstream kinases (MEK and ERK); AP-1 (activating protein-1)—is a transcription factor involved in differentiation, proliferation, cell survival and apoptosis; PI3K (phosphatidylinositol 3-kinase) together with Akt (Ak strain transforming) form an intracellular signaling pathway involved in cell metabolism, growth, proliferation and cell survival; PL-C (phospholipase C); DAG (diacylglycerol); PKC (protein kinase C)—kinase involved in the modulation of multiple regulatory molecules of the cell cycle.