Resistance to Anti-angiogenic Therapies: A Mechanism Depending on the Time of Exposure to the Drugs

Abstract

Angiogenesis, the formation of new blood vessels from preexisting one, represents a critical process for oxygen and nutrient supply to proliferating cells, therefore promoting tumor growth and metastasis. The Vascular Endothelial Growth Factor (VEGF) pathway is one of the key mediators of angiogenesis in cancer. Therefore, several therapies including monoclonal antibodies or tyrosine kinase inhibitors target this axis. Although preclinical studies demonstrated strong antitumor activity, clinical studies were disappointing. Antiangiogenic drugs, used to treat metastatic patients suffering of different types of cancers, prolonged survival to different extents but are not curative. In this review, we focused on different mechanisms involved in resistance to antiangiogenic therapies from early stage resistance involving mainly tumor cells to late stages related to the adaptation of the microenvironment.

The Anti-VEGF(R) Drug Discovery Legacy: Improving Attrition Rates by Breaking the Vicious Cycle of Angiogenesis in Cancer

“…As recently suggested by Montemagno and Pagés, the better approach might be the following: "Instead of inhibiting several targets with several drugs, the ideal strategy relies on the use of one inhibitor targeting multiple hallmarks of cancers, i.e., tumor cell proliferation/stemness, angiogenesis, chronic inflammation, and immune tolerance." [150].…”

“…Moreover, if we need to say why the effects of the anti-angiogenic drugs have been so disappointing so far, this is probably because of their use with a “carpet bombing” approach rather than using them according to the biology of the tumor. As recently suggested by Montemagno and Pagés, the better approach might be the following: “Instead of inhibiting several targets with several drugs, the ideal strategy relies on the use of one inhibitor targeting multiple hallmarks of cancers, i.e., tumor cell proliferation/stemness, angiogenesis, chronic inflammation, and immune tolerance.” [ 150 ].…”

Cancer Stem Cells—Key Players in Tumor Relapse

“…Different mechanisms have been associated with the development of antiangiogenic drug resistance, both primary and acquired [162]. Primary resistance can be due to the redundancy of angiogenetic pathways: several factors, such as EGFs, FGFs, TGFs, PDGFs, can contribute to the vascularization [162][163][164], compensating for VEGF blockade. One intriguing acquired mechanism exploited by cancer cells to escape antiangiogenic therapies is represented by the process of vasculogenic mimicry.…”

Anti-Angiogenic Therapy: Albumin-Binding Proteins Could Mediate Mechanisms Underlying the Accumulation of Small Molecule Receptor Tyrosine Kinase Inhibitors in Normal Tissues with Potential Harmful Effects on Health

“…Moreover, in many cases human tumors can induce their own microvasculature not only by sprouting angiogenesis but also through non-angiogenic mechanisms involving non-proliferating cells (e.g., co-option of pre-existing normal vessels, recruitment of bone-marrow-derived stem cells, and vasculogenic mimicry) that explain the resistance of tumors to conventional anti-angiogenic treatments [ 25 , 26 , 27 , 28 , 29 , 30 , 31 ]. These non-angiogenic mechanisms and the resistance mechanisms to common molecularly targeted agents (e.g., angiogenic redundancy, angiogenic dormancy, tumor metabolic adaptation) could explain the frequent inefficacy of the anti-angiogenic treatments with small molecule RTKIs and monoclonal therapeutic antibodies (reviewed in [ 32 , 33 ]).…”