Targeting angiogenesis in metastatic breast cancer

Abstract

Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.

Figure 1.

The angiogenic switch [–31]. Abbreviations: EGF, epidermal growth factor; FGF, fibroblast growth factor; PDGFB, platelet-derived growth factor B; VEGF, vascular endothelial growth factor. Reprinted with permission from Brufsky AM. Expanding the targets in adjuvant therapy. Clinical Care Options Oncology. Available at: http://www.clinicaloptions.com/Oncology/Treatment%20Updates/Bisphosphonates%20and%20Targeted%20Agents.aspx. Accessed July 16, 2012.

Figure 2.

Intracellular vascular endothelial growth factor (VEGF) signal transduction pathway. Ligands bind to membrane receptors, which are phosphorylated, leading to activation of several cytoplasmic messengers, which activate transcription factors in the nucleus that involves target genes implicated in the proliferation, angiogenesis, apoptosis, and tumor invasion. Shown are some targeted therapies and their main inhibition targets [–35]. ^aVEGF A–D ligands bind to VEGF receptors 1–3 with specific ligands preferentially binding to a specific receptor (e.g., VEGF A and C ligands bind to VEGF receptor 2); ^bmAb to VEGF A; ^ctargets VEGF A and B and placental growth factor (PlGF); ^dmAb to VEGF receptor 1; ^emAb to VEGF receptor 2. Abbreviations: AKT, protein kinase B; BCR-ABL, Philadelphia chromosome; BRaf, B-type RAF kinase; C-src, cellular sarcoma; Grb, growth factor receptor–bound protein; JAK/STAT, Janus kinases/signal transducers and activators of transcription; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; mTOR, mammalian target of rapamycin; PI(4,5)P2, phosphatidylinositol (3,4) biphosphate; PI(3,4,5)P3, phosphatidylinositol (3,4,5) triphosphate; PI3K, phosphatidylinositol 3-kinase; PTC, papillary thyroid cancer; PTEN, phosphatase and tensin homologue; RET, rearranged during transfection; Shc, Src homology 2 domain-containing transforming protein; Sos, son of sevenless protein. Adapted from [32]. Copyright 2010 Springer. Reprinted with kind permission from Springer Science+Business Media B.V.