Abstract
The concept that blood supply is required and necessary for cancer growth and spreading is intuitive and was firstly formalized by Judah Folkman in 1971, when he demonstrated that cancer cells release molecules able to promote the proliferation of endothelial cells and the formation of new vessels. This seminal result has initiated one of the most fascinating story of the medicine, which is offering a window of opportunity for cancer treatment based on the use of molecules inhibiting tumor angiogenesis and in particular vascular-endothelial growth factor (VEGF), which is the master gene in vasculature formation and is the commonest target of anti-angiogenic regimens. However, the clinical results are far from the remarkable successes obtained in pre-clinical models. The reasons of this discrepancy have been partially understood and well addressed in many reviews (Bergers and Hanahan, 2008; Bottsford-Miller et al., 2012; El-Kenawi and El-Remessy, 2013; Wang et al., 2015; Jayson et al., 2016). At present anti-angiogenic regimens are not used as single treatments but associated with standard chemotherapies. Based on emerging knowledge of the biology of VEGF, here we sustain the hypothesis of the efficacy of a dual approach based on targeting pro-angiogenic pathways and other druggable targets such as mutated oncogenes or the immune system.
Highlights
Reviewed by: Ronca Roberto, University of Brescia, Italy Anca Maria Cimpean, “Victor Babes” University of Medicine and Pharmacy Timisoara, Romania
This seminal result has initiated one of the most fascinating story of the medicine, which is offering a window of opportunity for cancer treatment based on the use of molecules inhibiting tumor angiogenesis and in particular vascular-endothelial growth factor (VEGF), which is the master gene in vasculature formation and is the commonest target of anti-angiogenic regimens
It has been recently reported that combined treatment with cetuximab and regorafenib induced synergistic anti-proliferative and pro-apoptotic effects by blocking MAPK and AKT pathways in orthotopic CRC xenograft models with primary or acquired resistance to anti-EGFR (Napolitano et al, 2015). This beneficial effect can be dependent on the inhibitor activities of regorafenib on different tyrosine kinase receptors involved in angiogenesis and potentially in the mechanism of resistance to cetuximab
Summary
Transcription is promoted by hypoxia-inducible factor-1α (HIF1α) and −2α (HIF2α) that sense the reduced pO2 (Semenza, 2009). Capillaries are tortuous, irregularly fenestrated with reduced pericyte coverage and leaky These morphological aberrations induce the increase of interstitial pressure with the decrease of convective transport of small molecules including chemotherapeutics (Nagy et al, 2006; Jain, 2014). Before reaching the whole collapse of vascular bed, VEGF pathway blockade is characterized by an early and transient phase in which vessels assume normal shape and function (Folkman, 2006; Carmeliet and Jain, 2011; Goel et al, 2011) This normalization is characterized by rescue of the balance between inhibitors and inducers of angiogenesis, reduction of leakage and interstitial pressure, improvement of tumor perfusion and oxygenation, and drug delivery. The multi-targeted kinase inhibitor sunitinib (VEGFRs, PDGFRs, FLT3, CSFF1R) has been approved for RCC and pancreatic neuroendocrine tumors (Table 1)
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