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Antibody-Based Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Angiogenesis is a vital process that facilitates tumor growth and survival. Tumor angiogenesis refers to the ability of a tumor to stimulate new blood vessel formation around it, which facilitates tumor expansion, local invasion, and metastasis through enhanced delivery of oxygen, nutrients, and survival factors, improved removal of CO2 and metabolic waste products, the production of growth factors that benefit tumor cells, and an enhanced route for metastases. Angiogenesis is stimulated by the Vascular Endothelium Growth Factor (VEGF) protein which interacts with the Vascular Endothelium Growth Factor Receptor (VEGFR) on the surface of tumor cells, thus stimulating angiogenesis (Figure 7.8).
Central Nervous System
Published in Pat Price, Karol Sikora, Treatment of Cancer, 2020
Gliomas are highly vascular tumors that rely on an enhanced blood supply for their rapid growth. Stimulation of the vascular endothelial growth factor receptor (VEGFR) by VEGF underpins this angiogenesis, promoting endothelial cell migration and proliferation and leading to the formation of new vessels. The vessels are abnormal, having large diameters, tortuous routes, decreased pericyte coverage, increased thickness of basement membrane, and altered transport properties. Anti-VEGF agents induce endothelial cell apoptosis and inhibition of new vessel formation while normalizing existing tumor vessels and decreasing permeability.
Imaging Angiogenesis
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
VEGF, as a central cytokine in the angiogenic process, mediates many cellular functions including release of other growth factors, endothelial cell proliferation, migration, and survival, which are essential in the development of new vasculature (i.e., during angiogenesis and tumorgenesis). There are at least five isoforms of human VEGF, which are either freely diffusible (i.e., VEGF165, VEGF145, and VEGF121) or cell-associated (i.e., VEGF206 and VEGF189). The VEGF receptor family consists of two principal receptors found on vascular endothelial cells, VEGFR-1 (or Flt-1) and VEGFR-2 (or Flk-1), and one receptor expressed on lymphatic endothelial cells (VEGFR-3) (Cross and Claesson-Welsh 2001).
New benzoxazole derivatives as potential VEGFR-2 inhibitors and apoptosis inducers: design, synthesis, anti-proliferative evaluation, flowcytometric analysis, and in silico studies
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Hazem Elkady, Alaa Elwan, Hesham A. El-Mahdy, Ahmed S. Doghish, Ahmed Ismail, Mohammed S. Taghour, Eslam B. Elkaeed, Ibrahim H. Eissa, Mohammed A. Dahab, Hazem A. Mahdy, Mohamed M. Khalifa
Growth factors, including vascular endothelial growth factors (VEGFs) and their receptors (VEGFRs), control angiogenesis5–7. Three main vascular endothelial growth factor receptor subtypes are well-defined namely, VEGFR-1, VEGFR-2, and VEGFR-38. These receptors are the key players' intermediates in controlling tumour angiogenesis and in the development of new blood vessel networks essential to supply nutrition and oxygen for tumour growth9. Among the three VEGFRs subtypes, VEGFR-2 plays the most critical role in promoting tumour angiogenesis10. Following its activation by VEGF, VEGFR-2 initiates downstream signal transduction via dimerisation and then autophosphorylation of tyrosine receptor. These signalling pathways result in tumour angiogenesis11. Thus, hindering the VEGF/VEGFR-2 signalling pathway or reducing its response by tyrosine kinases inhibitors (TKIs) is a supreme significant target in anti-angiogenesis therapy against cancer12. Over the last decades, several small molecules have been approved for obstructing this critical pathway in angiogenesis13,14. Development of tumour resistance to the effect of the current clinically used small-molecule TKIs opens the door for the investigation of the effectiveness of new chemotypes.
Cholangiocarcinoma: what are the most valuable therapeutic targets – cancer-associated fibroblasts, immune cells, or beyond T cells?
Published in Expert Opinion on Therapeutic Targets, 2021
Juan Wang, Emilien Loeuillard, Gregory J. Gores, Sumera I. Ilyas
Vascular endothelial growth factor receptor (VEGFR) promotes angiogenesis and invasiveness. High mobility group box 1 (HMGB1) released from cancer cells upregulates VEGFR-2 expression in CCA, resulting in tumor angiogenesis [22]. Apatinib, a tyrosine kinase inhibitor targeting VEGFR-2, suppresses CCA proliferation, migration, and angiogenesis [23]. These antitumor effects of apatinib are a consequence of VEGFR2/STAT3/HIF-1α axis inhibition. VEGF/VEGFR2 signaling also exerts anti-apoptotic effects in CCA via activation of the PI3K-Akt-mTOR signaling pathway. Apatinib inhibits this effect and promotes CCA cell apoptosis in vitro [24]. Given it has shown promsing effecacy in preclinical studies, aptinib has been evaluated in early phase human clinical trials. In a prospective, open-label phase II trial, patients with advanced CCA who received apatinib (n = 26) had an objective response rate (ORR) of 11.5% and disease control rate (DCR) of 50% [25]. Apatinib was evaluated in another prospective, open-label phase II trial of patients with advanced CCA who had progressed on gemcitabine-based systemic therapy [26]. In 24 patients, apatinib had an ORR of 20.8% and DCR of 62.5%. Although there have been a number of preclinical studies that have examined the protumor effects of CCA angiogenesis, the results of human clinical trials investigating anti-angiogenic drugs have been disappointing. A comprehensive and in-depth understanding of the complex biology of tumor vascularization is needed to design optimal therapies targeting angiogenesis in CCA.
Targeted therapy for solid tumors and risk of hypertension: a meta-analysis of 68077 patients from 93 phase III studies
Published in Expert Review of Cardiovascular Therapy, 2019
Matteo Santoni, Alessandro Conti, Francesco Massari, Vincenzo Di Nunno, Luca Faloppi, Eva Galizia, Jarno Morbiducci, Francesco Piva, Sebastiano Buti, Roberto Iacovelli, Benedetta Ferretti, Alessia Cimadamore, Marina Scarpelli, Antonio Lopez-Beltran, Liang Cheng, Nicola Battelli, Rodolfo Montironi
Among targeted agents, administration of angiogenesis inhibitors is often related to the development of hypertension and this is mainly, but not only, due to the inhibition of Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR). Indeed, binding of VEGF to VEGFR activates Phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), which induces phosphatidylinositol bisphosphate (PIP2) conversion to phosphatidylinositol (3,4,5)-trisphosphate (PIP3) and stimulate AKT. The latter, in turn, stimulates the endothelial nitric oxide synthase (eNOS) and increases nitric oxide (NO) production to promote vasodilatation, reduction of platelet aggregation and smooth muscle cell growth [6]. VEGFR is also expressed on endothelial, mesangial and peritubular capillary cells in kidney where is involved in cell proliferation and survival. Therefore, VEGF/VEGFR inhibition results in systemic vasoconstriction, loss of vascular permeability, endothelial and glomerular damage, which are also potential mechanisms of induced hypertension during treatment [6–9]. Other agents targeting Platelet-derived growth factor receptor (PDGFR)α could promote loss of pericytes, while mammalian Target of Rapamycin (mTOR) inhibition results in inhibition of renal glomerular hypertrophy and tubulointerstitial fibrosis [10–12].