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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Normally, VEGF binds to VEGF receptors (VEGFRs) on the surface of blood vessel endothelial cells, thus activating signaling pathways that encourage capillary growth (see lower panel, Figure 7.8). A marked increase in VEGF expression within the tumor environment stimulates the production of blood vessels, a process known as angiogenesis, essential for growth of a tumor (Upper panel, Figure 7.8). However, these blood vessels are usually not well formed and lead to poor blood flow in the tumor, which can also reduce the delivery of anticancer agents to the tumor cells. By blocking the interaction of VEGF with VEGFR, and other receptors such as Flt-1 and KDR, on the surface of endothelial cells, the proliferation of endothelial cells can be reduced. This means that formation of new blood vessels at the tumor site is reduced, and existing microvessels may regress. This can reduce the supply of nutrients to the tumor and inhibit the removal of waste products, thus limiting growth and reducing the risk of metastasis. There is some evidence that VEGF inhibition can also normalize existing tumor vasculature, which may explain why bevacizumab is particularly effective in combination with conventional drugs that may be able to reach the tumor cells more effectively as a result.
Renal Cell Cancer
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Seven agents targeting the VEGF receptor pathway are now licensed and in routine use for the treatment of advanced kidney cancer. Six licensed agents—sunitinib, pazopanib, axitinib, sorafenib, tivozanib, and cabozantinib—are multi-targeted tyrosine kinase inhibitors targeting VEGFR function and other related receptor signaling. The seventh licensed agent, bevacizumab, is a monoclonal antibody that is able to bind and neutralize circulating VEGF ligand.
Actions of Dopamine on the Skin and the Skeleton
Published in Nira Ben-Jonathan, Dopamine, 2020
Angiogenesis is a critical step in the complex sequence of events leading to dermal wound healing. Interactions between DA and vascular endothelial growth factor (VEGF) in the control of angiogenesis were studied using human umbilical vein endothelial cells (HUVECs), an established endothelial cell line [14]. DA inhibited VEGF-induced phosphorylation of the VEGF receptor 2 (VEGFR-2), and suppressed endothelial cell proliferation, migration, and microvascular permeability, resulting in the overall inhibition of angiogenesis. The postulated mechanism by which DA affects VEGF actions is illustrated in Figure 11.4. Under normal conditions, D2R co-localizes with VEGFR-2 at the cell surface. DA pretreatment increased the translocation of Src-homology-2-domain-protein tyrosine phosphatase (SHP-2) to the cell surface, where it co-localizes with D2R. The subsequent VEGF treatment stimulates SHP-2 phosphorylation, and with it, its phosphatase activity which dephosphorylates VEGFR-2. The involvement of SHP-2 in this process was confirmed by showing that SHP-2 knockdown impaired the DA-regulated inhibition of VEGF-induced phosphorylation of VEGFR-2 and cell migration. The authors concluded that this study established a novel role for SHP-2 phosphatase in the DA-mediated inhibition of angiogenesis.
An appraisal of vascular endothelial growth factor (VEGF): the dynamic molecule of wound healing and its current clinical applications
Published in Growth Factors, 2022
Aakansha Giri Goswami, Somprakas Basu, Farhanul Huda, Jayanti Pant, Amrita Ghosh Kar, Tuhina Banerjee, Vijay Kumar Shukla
However, such observations are not necessarily sacrosanct. Contradictory studies have shown that EPCs from diabetic patients are dysfunctional and display a pro-inflammatory phenotype thereby possessing a reduced potential to generate vascular regenerative cells (Caballero et al. 2007; Loomans et al. 2009). Considering the crucial role ECs play in angiogenesis, the traditional concept that vascular EC is the only target of VEGF is repudiated. A number of studies have suggested the presence of VEGF receptors on non-ECs such as neutrophils (Ancelin et al. 2004), monocytes (Barleon et al. 1996; Sawano et al. 2001), stromal cells (Decaussin et al. 1999), and keratinocytes (Wilgus et al. 2005), which indicates that besides angiogenesis, VEGF plays a more complex and wider pivotal role wound healing (Figures 2–4). The hypothesis is further strengthened by the observation that administration of antiangiogenic agents, which may be expected to impair wound vascularity, does not affect wound closure in various murine models (Jacobi et al. 2004; Roman et al. 2002; Tsou et al. 2002). This evidence opens up wide opportunity to explore other nonconventional therapeutic targets in recalcitrant diabetic wounds.
An updated patent review of VEGFR-2 inhibitors (2017-present)
Published in Expert Opinion on Therapeutic Patents, 2021
Thoraya A. Farghaly, Wedian A. Al-Hasani, Hanan Gaber Abdulwahab
Among the VEGF receptors, VEGFR-2 stands out as the most critical factor in promoting angiogenesis. VEGFR-2 is apparently hyper-activated or over-expressed in many types of solid tumors such as renal carcinoma, colorectal, and lung cancers [7–9]. As a druggable main player in cancer development, VEGFR-2 is well-recognized as the most important target for anti-angiogenesis therapy against cancer. Extensive efforts have been made for the design and development of small molecules VEGFR-2 inhibitors [10–13]. As a consequence, several VEGFR-2 inhibitors have reached the market, resulting in a great therapeutic response and numerous candidate drugs were also clinically tested [10–13]. For example, Sorafenib, a urea derivative, was clinically approved in 2005 for the treatment of metastatic renal cancer, hepatocellular carcinoma, and thyroid cancer. In 2006, the indoline derivative, Sunitinib, reached the clinic for the treatment of renal cell carcinoma, gastrointestinal stromal tumor, and non-small-cell lung carcinoma. Later on, Pazopanib was approved in 2009 as a VEGFR-2 inhibitor for the treatment of renal cell carcinoma and soft tissue sarcomas. Moreover, the quinolone derivatives; Lenvatinib, Vandetanib, Cabozantinib, are clinically used for the treatment of thyroid cancer, melanoma, renal cell carcinoma, kidney cancer, and prostate cancer [10–13].
Quantile-specific heritability of serum growth factor concentrations
Published in Growth Factors, 2021
Bevacizumab is a recombinant, humanized monoclonal antibody that suppresses angiogenesis by binding to VEGF-A, thereby preventing its interactions with the VEGF receptor (Mukherji 2010). Early serum VEGF reduction is a potential predictive marker of anti-VEGF therapy responsiveness (Schneider et al. 2008). Suenaga et al. (2019) reported that reductions in VEGF-A concentrations following bevacizumab treatment were significantly greater in G-allele carriers of the rs2280789 CCL5 (C–C motif chemokine ligand 5) polymorphism than AA homozygotes following 56 days of treatment, as shown in the histogram of Figure 3(A) (P = 0.03). However, the treatment significantly lowered average VEGF concentrations from 383.7 to 177.1 pg/ml. As shown in the line graph, the results could also be attributed in part to a smaller difference between genotypes at the lower post-treatment average VEGF concentrations vis-à-vis its pre-treatment average (i.e. AG/GG minus AA: 5.7 pg/ml post-treated versus 193.3 pg/ml pre-treated).