Antiangiogenic Therapies: Going beyond Their Limits

Abstract

Tumor growth requires induction of an angiogenic program, and targeting of this program with antiangiogenic drugs shows an impact on tumor progression. However, although they are effective at reducing angiogenesis, these therapies have not produced widespread or enduring clinical benefi t, which openly exposes their limitations. Here, we describe the current limitations of these therapies, including the known mechanisms and current controversies. Further, we present some of the recent approaches to predict these limitations and strategies to overcome them. With the development of meaningful predictive biomarkers and effective treatments that impede these limitations, longer and more robust effi cacies will be achieved for a wider population of patients. Signifi cance:The clinical benefi t of antiangiogenic drugs is restricted because of intrinsic and acquired limitations. Acknowledging and understanding these limitations will not only allow the development of effective predictive biomarkers but also help in devising new therapeutic strategies that achieve longer effi cacies for a wider population of patients. Cancer Discov; 4(1); 31-41.

Bevacizumab-Induced Inhibition of Angiogenesis Promotes a More Homogeneous Intratumoral Distribution of Paclitaxel, Improving the Antitumor Response

“…Targeting the VEGF-VEGFR signaling axis with ligand-binding drugs (i.e., with the antibody bevacizumab) or with low-molecular-weight VEGF receptor tyrosin kinase inhibitors (TKI) shows efficacy in different tumor types, though the survival benefit associated to these class of drugs is modest. At variance with the TKI, which are in general given as single-agent therapy, bevacizumab, in most settings, requires the addition of cytotoxic therapy (2,3). It has particularly beneficial effect when combined with chemotherapy, prolonging overall survival (OS) in patients with metastatic colorectal cancer (4), recurrent/ advanced non-small cell lung cancer (NSCLC; ref.…”

Identification of an Endogenously Generated Cryptic Collagen Epitope (XL313) That May Selectively Regulate Angiogenesis by an Integrin Yes-associated Protein (YAP) Mechano-transduction Pathway

“…Efforts are underway to more precisely define the interconnected mechanisms that control this crucial biological process to develop more effective strategies to control neovascular diseases (1,2). Significant advances have been made in identifying molecular regulators of angiogenesis and their associated signaling pathways (3)(4)(5). A more precise understanding of angiogenic signaling pathways and the networks of regulatory feedback loops operating within distinct cellular compartments has provided important clues to help explain the modest clinical impact of many current anti-angiogenic strategies (1)(2)(3)(4)(5).…”

“…Significant advances have been made in identifying molecular regulators of angiogenesis and their associated signaling pathways (3)(4)(5). A more precise understanding of angiogenic signaling pathways and the networks of regulatory feedback loops operating within distinct cellular compartments has provided important clues to help explain the modest clinical impact of many current anti-angiogenic strategies (1)(2)(3)(4)(5). For example, although vascular endothelial growth factor (VEGF) induces pro-angiogenic signaling leading to enhanced endothelial cell migration, growth, and survival, VEGF-induced blood vessels are often characterized as immature, unstable, and leaky and can regress in the absence of additional signaling events (6).…”

Anti-VEGF Therapy in Cancer: A Double-Edged Sword

“…Tumors can acquire resistance to the drugs (if they do not already have intrinsic resistance) and demonstrate an increase in aggressiveness. Moreover, antiangiogenic therapies may cause a decrease in chemotherapy perfusion, lowering the eicacy of chemotherapies given in combination with antiangiogenic medicine [123]. These diiculties suggest that, at least when given alone, antiangiogenic therapies may face severe limitations in survival beneits.…”

“…Therefore, future research should focus on more than simply inhibiting VEGF on a continuous schedule. Rather, it should focus on increasing the eicacy of chemotherapy through utilizing antiangiogenic therapy to induce vascular normalization, allowing for more eicient delivery of chemotherapeutic agents [123,124]. Moreover, research should also ind ways to decrease resistance to these therapies through inhibiting proangiogenic factors that are upregulated in response to the inhibition of VEGF and through developing predictive biomarkers for the eicacy of these expensive treatments [123,124].…”