Angiogenesis Inhibitors for Colorectal Cancer. A Review of the Clinical Data

Abstract

Since the late 1990s, therapy for metastatic colorectal cancer (mCRC) has changed considerably, and the combination of doublet or triplet chemotherapy and a targeted agent are now routinely used. The targeting of angiogenesis, the development of new blood vessels, represents a key element in the overall treatment strategy. Since the approval in 2004 of the first anti-angiogenetic drug, multiple agents have been approved and others are currently under investigation. We present an overview of the recent literature on approved systemic treatment of mCRC, with a focus on anti-angiogenic drugs, and current treatment approaches, and elaborate on the future role of angiogenesis in colorectal cancer as seen from a clinical perspective. The treatment of mCRC, in general, has changed from “one strategy fits all” to a more personalized approach. This is, however, not entirely the case for anti-angiogenetic treatments, partly due to a lack of validated biomarkers. The anti-angiogenetic standard treatment at the present primarily includes monoclonal antibodies. The therapeutic field of angiogenesis, however, has received increased interest after the introduction of newer combinations. These approaches will likely change the current treatment strategy, once again, to the overall benefit of patients.

EGR1 Enhances Lymphangiogenesis via SOX18-Mediated Activation of JAK2/STAT3 Pathway

“…Both blood and lymphatic structures are lined with endothelial cells that communicate with the extracellular environments [ 28 ]. Angiogenesis and lymphangiogenesis often occur pathological conditions such as inflammation, tissue injury, and tumor growth [ 29 ], and both of them are responded to multiple inducers or inhibitors [ 19 , 30 , 31 ]. A number of studies have been reported that factors involved in angiogenesis also have an effect on lymphangiogenesis.…”

Emerging actionable targets to treat therapy-resistant colorectal cancers

“…The first anti-angiogenic agent entering the clinic for the treatment of mCRC has been bevacizumab, a humanized monoclonal antibody anti-VEGF-A which binds circulating VEGF-A and blocks the interaction with its cell surface receptors (VEGFR1 and 2), thus reducing microvascular growth and inhibiting the blood supply to the tumor tissues [140] . In recent years the development of anti-angiogenic agents has increased, leading to the addition to of aflibercept (second-line treatment for advanced CRC) and regorafenib (in patients with mCRC who have already received chemotherapy and other targeted therapies).…”

“…Regorafenib is multi-kinase inhibitor targeting angiogenic, stromal, and oncogenic receptor tyrosine kinase that shows strong anti-angiogenic activity due to its dual targeted VEGFR2-TIE2 tyrosine kinase inhibition. In addition, other anti-angiogenic drugs are in preclinical and clinical phase I-III studies [ 141 ] .…”

Dual Inhibition of Myc Transcription and PI3K Activity Effectively Targets Colorectal Cancer Stem Cells

“…Recently, we demonstrated that about 50% of BRAF and RAS wt CRC sphere cells (CR-CSphCs) are resistant to cetuximab treatment due to high expression levels of CD44v6 [11,17]. Many other therapeutic strategies, including anti-angiogenic drugs and Met pathway and immune checkpoint inhibitors, are currently under evaluation for managing CRC treatment [2,[18][19][20][21]. Another common mechanism of resistance to standard and targeted therapies is gene amplification/overexpression [22][23][24].…”