Therapy for Cancer: Strategy of Combining Anti-Angiogenic and Target Therapies

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.

Resistance Mechanisms to Anti-angiogenic Therapies in Cancer

“…Several preclinical studies revealed the anti-angiogenic benefits when inhibiting TGFβ in CRC, HCC, and GBM xenografts (189)(190)(191). This offers the rationale to combine TGFβ inhibitors with anti-VEGF agents (192).…”

Significance of Targeting VEGFR-2 and Cyclin D1 in Luminal-A Breast Cancer

“…Angiogenesis is one of the important hallmarks of cancer [ 24 ], and ER is an essential agonist and inducer of angiogenesis signaling pathways [ 25 ]. Angiogenesis can be inhibited by the VEGFR-2 signaling pathway inhibitors like sorafenib or sunitinib.…”

“…Interestingly, the anti-VEGF-A drug bevacizumab failed to improve patients’ overall survival as a monotherapy at first, thus it was combined with paclitaxel for the HER2 - metastatic BC and got Food and Drug Administration (FDA) approval, before withdrawal of this combination again due to efficacy issues and acquired resistance. Thus, new combinations that can show stronger effects on major hallmarks of cancer, like the cell cycle and apoptosis, are needed to overcome the drawbacks of the previous anti-VEGFR combinations [ 24 ].…”

Molecular Links Between Angiogenesis and Neuroendocrine Phenotypes in Prostate Cancer Progression

“…Angiogenic activators include angiopoietins, CCL2, EGFL6, endothelins, FGF, HIF1, IGF1, MMPs, PDGF, TGF, VEGF, and et al (48)(49)(50)(51)(52)(53)(54)(55)(56). On the other hand, angiostatin, endostatin, TSP1, and PAI2 are among the endogenous inhibitors of angiogenesis (57)(58)(59)(60).…”

“…Due to the striking pathological similarity between SCLC and NEPC, it is likely that, for NEPC, finding the right combinations of anti-angiogenesis and other therapies will be key to achieve significant efficacy for NEPC. Several strategies of combining anti-angiogenic regimens with targeted/chemo/immune therapies have been or are being tested clinically in several cancer types (59). These strategies include combining different anti-angiogenic regimens, simultaneously inhibiting angiogenesis and driving oncogenes, or combining anti-angiogenic regimens with immunotherapy.…”