The Role of Antiangiogenetic Agents in the Treatment of Breast Cancer

Abstract

Angiogenesis is known to be essential for the development and progression of cancer. Vascular endothelial growth factor (VEGF) is a critical mediator in tumor angiogenesis for many solid malignancies, including breast cancer. Increased levels of VEGF have been associated with poor clinical outcomes, including reduced survival. VEGF has become an attractive target for cancer therapy in view of its pivotal role in angiogenesis. The primary approaches for inhibiting angiogenesis have focused on inhibiting the activity of VEGF, either by targeting the VEGF ligand itself with monoclonal antibodies (mAbs) or by interfering with the signaling events downstream of VEGF through the use of tyrosine kinase inhibitors (TKIs). Bevacizumab is a recombinant, humanized monoclonal IgG1, anti-VEGF antibody that has demonstrated significant clinical benefit in several solid tumors. Bevacizumab has been approved for use in combination with paclitaxel for the first line treatment of patients with metastatic breast cancer (MBC) based on the results of the randomized phase III E2100 trial in which it improves response rate and time to progress when administered with weekly paclitaxel until disease progression. Several trials to define the role of bevacizumab in different setting of disease and in combination with different chemotherapy regimens and targeted therapy in breast cancer patients are ongoing. Other small molecule inhibitors of VEGF tyrosine kinase activity (TKIs) such as sunitinib, vandetanib and sorafenib are being tested in MBC. This review will focus on bevacizumab and on the developements of the main antiangiogenic agents in the treatment of breast cancer.

Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

“…On the other hand, drugs that interfere with growth factor signalization include trastuzumab, gefitinib, lapatinib, inhibitors of farnesyltrasferase, inhibitors of the mammalian target of rapamycin and multitargeted tyrosine inhibitors [253]. Endocrine therapy is also being clinically tested in combination with antiangiogenic factors such as bevacizumab (a humanized monoclonal antibody that inhibits VEGF-A) and motesanib (an oral inhibitor of VEGF receptors) [253,255,256]. …”

In Vitro and In Vivo Models for Analysis of Resistance to Anticancer Molecular Therapies

“…Unconventional mechanisms mediate resistance to another class of molecular drugs, the anti-angiogenic agents [16, 17]. Evasion of anti-angiogenic therapy is indeed largely indirect.…”

Bevacizumab in advanced breast cancer

“…Its mechanism of action is to prevent the binding of VEGF to its receptors Flt-1 (VEGFR-1) and KDR (VEGFR-2), located on the surface of endothelial cells [12]. Its mechanism of action is to prevent the binding of VEGF to its receptors Flt-1 (VEGFR-1) and KDR (VEGFR-2), located on the surface of endothelial cells [12].…”