Effects Of Antiangiogenic Agents Research Articles

Assessment of Antiangiogenic and Cytotoxic Effects of Moringa oleifera Silver Nanoparticles Using Cell Lines

Angiogenesis is the physiological process through which new blood vessels are developed from pre-existing vessels. It includes steps like migration, differentiation, and growth of endothelial cells. Furthermore, it plays a critical role in cancer formation and metastasis. Recently, Moringa oleifera (MO) has gained interest due to its properties in various fields, particularly in nanoparticle (NP) technology. This study aims to demonstrate the cytotoxic and antiangiogenic effects of MO silver nanoparticles (MO-AgNPs). Briefly, the cytotoxic effects of MO-AgNPs on Ea. hy 926 and HT 29 cell lines were observed in the Colony Formation Assay. The antiproliferative effects of MO-AgNPs were then further confirmed using MTT assay, in addition to morphological characterization, migration and closure percent calculation. To evaluate the antiangiogenic effect of MO, the chorioallantoic membrane (CAM) assay was done. Fertilized chicken eggs were divided into three groups: MO-AgNPs, MO ethanol extract and negative control. The results showed antiangiogenic effects were observed at 6-12 µg/mL concentration of MO-AgNPs. Whereas the plate efficiency was 45.7 % ± 1%. The surviving fraction at 12, 6, 3, and 1.5 μg/mL was 27.3± 0.5%, 30.1 ± 0.5 %, 41.8 ± 1.5%, and 69.8 ± 2.5 %, respectively. MO-AgNPs showed higher cytotoxic activity than MO ethanol extract on the Ea. hy926 cell line, where the IC50 of MO-AgNPs were 74, 35, and 12 µg/mL for 24, 48 and 72 hours, respectively. On the other hand, the IC50 of MO ethanol extract was above 200, 135 and 11 µg/mL for 24, 48 and 72 hours, respectively. Additionally, significant morphological changes were observed in Ea. hy cells. Whereas the closure percent average of Ea. hy cells at 1.5, 3, 6, and 12 µg/mL were 91.603, 88.507, 84.599, and 63.144%, respectively. Based on the results showed in this study, MO extract shows potential to be an effective anti-angiogenic agent and is a promising therapeutic option in cancer treatment.

Assessing the Antiangiogenic Effects of Chalcones and Their Derivatives

Pathological angiogenesis plays a critical role in tumorigenesis and tumor progression, and anti-angiogenesis therapies have evinced promising antitumor effects in solid tumors. Chalcone skeleton has been regarded as a potential antitumor agent that also targets angiogenesis. In this study, we designed twenty-one non-fluoro-substituted chalcones (13–18, 24–27) and saturated chalcone derivatives (19–23, 28–33) as anti-angiogenic compounds. During the initial stage, these compounds were assessed for their anti-cancer activities against MCF-7 cancer cell lines according to the MTT assay. The compounds revealed satisfactory anti-proliferative capability. An ex vivo fertilized hens’ egg-chorioallantoic membrane (HET-CAM) angiogenic study was conducted for the compounds to gauge their mortality and toxicity, which, in turn, revealed a potent anti-angiogenic effect. Eight compounds (16, 17, 21, 24, 26, 27, 29, and 31) significantly reduced densities of capillaries on CAM, whereas compounds 27 and 29 were the most effective anti-angiogenic agents, when compared with Suramin. Moreover, RT-qPCR analysis demonstrated that the anti-angiogenic activity was associated with the fold changes of VEGFR2. Molecular docking studies were conducted for compounds to investigate their mode of interaction within the binding site of VEGFR-2 kinases. This work provided a basis for further design, structural modification, and development of chalcone derivatives as new anti-angiogenic agents.

Anti-angiogenic potential of bioactive phytochemicals from Helicteres isora targeting VEGFR-2 to fight cancer through molecular docking and molecular dynamics simulation

Cancer is one of the leading causes of death due to its very high rate of morbidity and mortality, and there is a constant demand of effective drugs for cancer therapy. Vascular endothelial growth factor receptor-2 (VEGFR-2) plays a significant role as central modulator of angiogenesis and is targeted frequently for developing anti-angiogenic agents to fight cancer. Helicteres isora L. (Malvaceae) is reported to possess diverse medicinal properties including anti-cancer potentials. In the current investigation, 38 bioactive phytochemicals of H. isora were screened virtually to evaluate their anti-angiogenic potentials targeting VEGFR-2. The study unveiled three potential candidates such as, Diosgenin (-9.8 Kcal//mol), Trifolin (-8.4 Kcal/mol) and Yohimbine (-8.1 Kcal/mol) that showed favorable pharmacokinetic, pharmacodynamic and toxicity properties with no significant side effects. Molecular dynamics simulation employing 100 ns revealed noteworthy structural stability and compactness for all the top three candidates. The MM/GBSA binding free energy estimation corroborated the docking interactions where Yohimbine (-30.47 Kcal/mol) scored better than Diosgenin (-27.54 Kcal/mol) and Trifolin (-29.58 Kcal/mol). Target class prediction revealed enzymes in most of the cases and some FDA approved drugs were found as structurally similar analogs for Trifolin and Yohimbine. These findings could lead to the development of novel and effective anti-angiogenic agents. Communicated by Ramaswamy H. Sarma

A comprehensive systematic review and network meta-analysis: the role of anti-angiogenic agents in advanced epithelial ovarian cancer

The efficacy of anti-angiogenic agents (AAAs) in epithelial ovarian cancer (EOC) remains unclear. Therefore, we conducted a systematic review and network meta-analysis (NMA) to synthesize evidence of their comparative effectiveness for improving overall survival (OS) among EOC patients. We searched six databases for randomized controlled trials (RCTs) from their inception to February 2021. We performed an NMA with hazard ratios (HRs) and 95%-confidence intervals (CIs) to evaluate comparative effectiveness among different AAAs in chemotherapy-naïve and recurrent EOC. P-score was used to provide an effectiveness hierarchy ranking. Sensitivity NMA was carried out by focusing on studies that reported high-risk chemotherapy-naïve, platinum-resistant, and platinum-sensitive EOC. The primary outcome was OS. We identified 23 RCTs that assessed the effectiveness of AAAs. In recurrent EOC, concurrent use of trebananib (10 mg/kg) with chemotherapy was likely to be the best option (P-score: 0.88, HR 1.67, 95% CI 0.94; 2.94). The NMA indicated that bevacizumab plus chemotherapy followed by maintenance bevacizumab (P-score: 0.99) and pazopanib combined with chemotherapy (P-score: 0.79) both had the highest probability of being the best intervention for improving OS in high-risk chemotherapy-naïve and platinum-resistant EOC, respectively. AAAs may not play a significant clinical role in non-high-risk chemotherapy-naïve and platinum-sensitive EOC.

Chebulinic acid is a safe and effective antiangiogenic agent in collagen-induced arthritis in mice

BackgroundAlthough vascular endothelial growth factor-A (VEGF)-induced angiogenesis has been reported to play an important role in the pathogenesis of rheumatoid arthritis (RA), serious side effects, mainly grade 2–3 hypertension, which is commonly observed with currently available anti-VEGF agents, can be detrimental for RA patients due to hypertension and associated cardiovascular complications seen in these patients. Thus, identification of anti-VEGF molecules that do not increase blood pressure could be useful for the treatment of RA. Chebulinic acid (CI), a water-soluble small-molecule tannin, can inhibit the actions of VEGF, and a report suggested that CI might not increase blood pressure due to its compensatory effects on the cardiovascular system. Therefore, the effects of CI on blood pressure in mice and the progression of the disease in a murine collagen-induced arthritis (CIA) model were investigated.MethodsCIA was induced in DBA/1J mice with type II collagen. The effects of CI in these animals were then evaluated by determination of clinical, histopathological, and immunohistochemical parameters. The effects of CI on VEGF-induced proangiogenic genes and signaling pathways were examined in vitro and in vivo.ResultsSignificant CD31 and VEGF expressions were detected in the synovial tissues of mice with CIA, similar to their expressions observed in human RA patients. However, treatment with CI significantly inhibited paw swelling, decreased the mean articular index and joint pathology scores in these animals through inhibition of VEGF-induced proangiogenic gene expressions and signaling pathways that regulate angiogenesis. Unlike currently used antiangiogenic agents, CI at a dose that inhibits VEGF actions did not increase blood pressure in mice.ConclusionCI can act as a safe and potent anti-VEGF antiangiogenic agent for the treatment of types of inflammatory arthritis, such as RA.

Dual Targeting of VEGFR2 and C-Met Kinases via the Design and Synthesis of Substituted 3-(Triazolo-thiadiazin-3-yl)indolin-2-one Derivatives as Angiogenesis Inhibitors.

The vascular endothelial growth factor receptor 2 (VEGFR2) and c-mesenchymal epithelial transition factor (c-Met) are members of receptor tyrosine kinases which have a crucial role in the process of angiogenesis. Isatin moiety is a versatile group that is shared in many compounds targeting both c-Met and VEGFR2 kinases. In this study, we designed and synthesized different derivatives of substituted 3-(triazolo-thiadiazin-3-yl)indolin-2-one derivatives (6a–y) as dual inhibitors for c-Met and VEGFR2 enzymes. Eight compounds 6a, 6b, 6e, 6l, 6n, 6r, 6v, and 6y were assessed for their anticancer activities against a panel of 58 cancer cell lines according to the US-NCI protocol. Compound 6b revealed the most effective antiproliferative potency (GI %), with broad-spectrum activity against different subpanels of the most NCI 58 tumor cell lines. An in vivo hen’s egg-chorioallantoic membrane (HET-CAM) angiogenic study was carried out for 21 compounds 6a, b, d, f, h, i, k–o, t, and 6x to check their mortality and toxicity. At 100 μM concentration, all compounds produced 100% mortality of the chick embryos. At 40 μM concentration, 13 compounds did not exhibit any detectable mortality (nontoxic) and revealed a potent antiangiogenic effect. Seven compounds 6b, 6d, 6f, 6n, 6o, 6t, and 6x significantly decreased the number of blood vessels, and compound 6b was the most effective antiangiogenic agent comparable to dexamethasone. Molecular docking studies were conducted for compound 6b to investigate its mode of interaction within the binding site of both c-Met and VEGFR2 kinases.

Abstract P4-10-28: Identification of a specific epigenetic signature in patients showing secondary hypertension upon anti-VEGF treatment from the GEICAM/2011-04 (BRECOL) study

Abstract BACKGROUND The appearance of secondary hypertension (HTN) is one of the most common side effects of anti-angiogenic agents since it emerges in over 50% of the patients with these therapies. Independently of tumor type, in most clinical trials it was possible to observe a positive association between secondary HTN and better clinical outcome, including Progression Free Survival (PFS) and Overall Survival (OS). Preeclampsia is one of the biological models that better resembles the anti-VEGF/VEGFR action of these therapies. DNA methylation is one of the epigenetic mechanisms potentially related to variation in susceptibility to gestational HTN. The objective of our study is to define a specific epigenetic signature that could predict secondary HTN to anti-angiogenic treatment in patients that received bevacizumab in combination with chemotherapy (CT) from the BRECOL study. METHODS Patients (n=113) from BRECOL study (NCT01733628) received bevacizumab in combination with oxaliplatin or irinotecan + fluoropyrimidines for metastatic colorectal cancer (n=49), and with paclitaxel or capecitabine for metastatic breast cancer (n=64). Blood pressure (BP) was recorded with a Holter measurement (24 hours registration starting 2 hours after treatment administration). A methylation analysis was carried out on DNA obtained from pretreatment peripheral blood samples in 32 patients (28%) distributed in 4 experimental groups (8 patients / each) and classified according to their HTN history and to their BP variation upon bevacizumab plus CT: • Group A: patients with HTN history and with BP increase • Group B: patients with HTN history and with no BP increase • Group C: patients without HTN history and with BP increase • Group D: patients without HTN history and with no BP increase Analysis was realized with the “Infinium Human Methylation EPIC BeadChip” array (Illumina®) on bisulfite-converted DNA and differentially methylated sites were identified with the LIMMA (“Linear Models for Microarray Analysis”) bioinformatics tool (Bioconductor®). RESULTS Upon analysis of 850000 different methylation sites distributed all over the genome, we identified 27 (18 localized in the coding regions of the genes: FMNL2, METTL3, ACOT6, SCARNA20, PREX1, DNAI2, RAET1G, KCNJ8, GDF7, SYNPO2, CUGBP1, FRMD8, MKL2, HIF1A, TMEM177, UTP23, PXK and TNPO1; 9 localized in intergenic regions) that are differentially methylated in patients that showed secondary HTN to bevacizumab plus CT, independently of HTN history (Groups A + C vs. B + D). Based on Principal Components (PC) analysis, we defined a methylation score predictive of elevated BP. First PC (PC1) explains the 83.2% of the variability of the 27 identified methylation sites and allows to distinguish between patients that do and do not show secondary HTN. CONCLUSIONS High BP upon anti-angiogenic treatment is associated to specific DNA methylation profiles. We identified an epigenetic methylation signature putative predictive of secondary HTN to bevacizumab treatment in metastatic breast and colorectal cancer. Citation Format: Juan de la Haba, Teresa Morales-Ruiz, Pilar García-Alfonso, Jose Ponce Lorenzo, Lourdes Calvo, Antonio Antón, Raul Marquez, Pedro Sánchez-Rovira, Ana Santaballa, Eva Ciruelos, María Victoria García-Ortiz, Teresa Roldán-Arjona, Jesús Herranz, Massimo Chiesa, Rosalía Caballero, Javier Gallego, Álvaro Rodríguez-Lescure. Identification of a specific epigenetic signature in patients showing secondary hypertension upon anti-VEGF treatment from the GEICAM/2011-04 (BRECOL) study [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P4-10-28.

UPARANT is an effective antiangiogenic agent in a mouse model of rubeosis iridis

Puncture-induced iris neovascularization (rubeosis iridis; RI) in mice is associated with upregulation of extracellular matrix (ECM) degradation and inflammatory factors. The anti-angiogenic and anti-inflammatory efficacy of UPARANT in reducing RI was determined by noninvasive, in vivo iris vascular densitometry, and confirmed in vitro by quantitative vascular-specific immunostaining. Intravitreal administration of UPARANT successfully and rapidly reduced RI to non-induced control levels. Molecular analysis revealed that UPARANT inhibits formyl peptide receptors through a predominantly anti-inflammatory response, accompanied with a significant reduction in ECM degradation and inflammation markers. Similar results were observed with UPARANT administered systemically by subcutaneous injection. These data suggest that the tetrapeptide UPARANT is an effective anti-angiogenic agent for the treatment of RI, both by local and systemic administrations. The effectiveness of UPARANT in reducing RI in a model independent of the canonical vascular endothelial growth factor (VEGF) proposes an alternative for patients that do not respond to anti-VEGF treatments, which could improve treatment in proliferative ocular diseases.Key messagesUPARANT is effective in the treatment of rubeosis iridis, both by local and systemic administrations.UPARANT can reduce VEGF-independent neovascularization.

Anti-angiogenesis for cancer: Current status and prospects

Since the establishment of tumor angiogenesis as a therapeutic target, new, effective antiangiogenic agents have been developed. Despite their demonstrable clinical benefits, these therapies often have only a short-term effect, with limited impact on the overall survival of cancer patients. A question in the development of these drugs concerns their optimal use in combination regimens with newer therapeutic strategies. Here we review the current therapeutic settings combining anti-angiogenesis inhibitors with chemotherapy, PARP inhibitors or immune checkpoint blockers, focusing on ovarian cancer as tumor model.

18F]FET PET is a useful tool for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic glioblastoma mouse model

O-2-18F-fluoroethyl-l-tyrosine ([18F]FET) has been widely used for glioblastomas (GBM) in clinical practice, although evaluation of its applicability in non-clinical research is still lacking. The objective of this study was to examine the value of [18F]FET for treatment evaluation and prognosis prediction of anti-angiogenic drug in an orthotopic mouse model of GBM. Human U87MG cells were implanted into nude mice and then bevacizumab, a representative anti-angiogenic drug, was administered. We monitored the effect of anti-angiogenic agents using multiple imaging modalities, including bioluminescence imaging (BLI), magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET/CT). Among these imaging methods analyzed, only [18F]FET uptake showed a statistically significant decrease in the treatment group compared to the control group (P=0.02 and P=0.03 at 5 and 20 mg/kg, respectively). This indicates that [18F]FET PET is a sensitive method to monitor the response of GBM bearing mice to anti-angiogenic drug. Moreover, [18F]FET uptake was confirmed to be a significant parameter for predicting the prognosis of anti-angiogenic drug (P=0.041 and P=0.007, on Days 7 and 12, respectively, on Pearson’s correlation; P=0.048 and P=0.030, on Days 7 and 12, respectively, on Cox regression analysis). However, results of BLI or MRI were not significantly associated with survival time. In conclusion, this study suggests that [18F]FET PET imaging is a pertinent imaging modality for sensitive monitoring and accurate prediction of treatment response to anti-angiogenic agents in an orthotopic model of GBM.

Monitoring and Targeting Anti-VEGF Induced Hypoxia within the Viable Tumor by 19F–MRI and Multispectral Analysis

The effect of anti-angiogenic agents on tumor oxygenation has been in question for a number of years, where both increases and decreases in tumor pO2 have been observed. This dichotomy in results may be explained by the role of vessel normalization in the response of tumors to anti-angiogenic therapy, where anti-angiogenic therapies may initially improve both the structure and the function of tumor vessels, but more sustained or potent anti-angiogenic treatments will produce an anti-vascular response, producing a more hypoxic environment. The first goal of this study was to employ multispectral (MS) 19F–MRI to noninvasively quantify viable tumor pO2 and evaluate the ability of a high dose of an antibody to vascular endothelial growth factor (VEGF) to produce a strong and prolonged anti-vascular response that results in significant tumor hypoxia. The second goal of this study was to target the anti-VEGF induced hypoxic tumor micro-environment with an agent, tirapazamine (TPZ), which has been designed to target hypoxic regions of tumors. These goals have been successfully met, where an antibody that blocks both murine and human VEGF-A (B20.4.1.1) was found by MS 19F–MRI to produce a strong anti-vascular response and reduce viable tumor pO2 in an HM-7 xenograft model. TPZ was then employed to target the anti-VEGF-induced hypoxic region. The combination of anti-VEGF and TPZ strongly suppressed HM-7 tumor growth and was superior to control and both monotherapies. This study provides evidence that clinical trials combining anti-vascular agents with hypoxia-activated prodrugs should be considered to improved efficacy in cancer patients.

Abstract 1801: Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts

Abstract Background: Studies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse. The purpose of this study was to compare the effect of properdistatin and sunitinib treatment in a preclinical model of malignant melanoma. Properdistatin is a small peptide derived from the thrombospondin-1 domain of the plasma protein properdin, and sunitinib is a tyrosine kinase inhibitor targeting several receptors including the vascular endothelial growth factor receptors. Methods: R-18 human melanoma xenografts growing in dorsal window chambers were treated with properdistatin, sunitinib, or vehicle. Parameters describing the morphology of tumor vasculature were assessed from high-resolution transillumination images, and BST (blood supply time; the time needed for arterial blood to flow from the main supplying artery to downstream microvessels) was assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by using pimonidazole as a hypoxia marker. Results: Properdistatin treatment selectively removed small-diameter vessels and reduced BST, whereas sunitinib treatment reduced the density of small- and large-diameter vessel similarly and did not change BST. These observations imply that properdistatin treatment reduced geometric resistance to blood flow and improved vascular function, whereas sunitinib treatment did not affect vascular function. Accordingly, sunitinib-treated tumors showed higher hypoxic fractions than properdistatin-treated tumors. Conclusions: Properdistatin and sunitinib both inhibited angiogenesis, but had distinctly different effects on vascular morphology, vascular function, and extent of hypoxia in R-18 human melanoma xenografts. Citation Format: Jon-Vidar Gaustad, Trude G. Simonsen, Lise Mari K. Andersen, Einar K. Rofstad. Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1801. doi:10.1158/1538-7445.AM2017-1801

Antiangiogenic agents targeting different angiogenic pathways have opposite effects on tumor hypoxia in R-18 human melanoma xenografts

BackgroundStudies comparing the effect of antiangiogenic agents targeting different angiogenic pathways are sparse. The purpose of this study was to compare the effect of properdistatin and sunitinib treatment in a preclinical model of malignant melanoma. Properdistatin is a small peptide derived from the thrombospondin-1 domain of the plasma protein properdin, and sunitinib is a tyrosine kinase inhibitor targeting several receptors including the vascular endothelial growth factor receptors.MethodsR-18 human melanoma xenografts growing in dorsal window chambers were treated with properdistatin, sunitinib, or vehicle. Parameters describing the morphology of tumor vasculature were assessed from high-resolution transillumination images, and BST (blood supply time; the time needed for arterial blood to flow from the main supplying artery to downstream microvessels) was assessed from first-pass imaging movies recorded after a bolus of fluorescence-labeled dextran had been administered intravenously. Tumor hypoxia was assessed from immunohistochemical preparations of the imaged tissue by using pimonidazole as a hypoxia marker.ResultsProperdistatin treatment selectively removed small-diameter vessels and reduced BST, whereas sunitinib treatment reduced the density of small- and large-diameter vessel similarly and did not change BST. These observations imply that properdistatin treatment reduced geometric resistance to blood flow and improved vascular function, whereas sunitinib treatment did not affect vascular function. Accordingly, sunitinib-treated tumors showed higher hypoxic fractions than properdistatin-treated tumors.ConclusionsProperdistatin and sunitinib both inhibited angiogenesis, but had distinctly different effects on vascular morphology, vascular function, and extent of hypoxia in R-18 human melanoma xenografts.

Growth of MCF-7 breast cancer cells and efficacy of anti-angiogenic agents in a hydroxyethyl chitosan/glycidyl methacrylate hydrogel

BackgroundBreast cancer negatively affects women’s health worldwide. The tumour microenvironment plays a critical role in tumour initiation, proliferation, and metastasis. Cancer cells are traditionally grown in two-dimensional (2D) cultures as monolayers on a flat solid surface lacking cell–cell and cell–matrix interactions. These experimental conditions deviate from the clinical situation. Improved experimental systems that can mimic the in vivo situation are required to discover new therapies, particularly for anti-angiogenic agents that mainly target intercellular factors and play an essential role in treating some cancers.MethodsChitosan can be modified to construct three-dimensional (3D) tumour models. Here, we report an in vitro 3D tumour model using a hydroxyethyl chitosan/glycidyl methacrylate (HECS–GMA) hydrogel produced by a series of chitosan modifications. Parameters relating to cell morphology, viability, proliferation, and migration were analysed using breast cancer MCF-7 cells. In a xenograft model, secretion of angiogenesis-related growth factors and the anti-angiogenic efficacy of Endostar and Bevacizumab in cells grown in HECS–GMA hydrogels were assessed by immunohistochemistry.ResultsHydroxyethyl chitosan/glycidyl methacrylate hydrogels had a highly porous microstructure, mechanical properties, swelling ratio, and morphology consistent with a 3D tumour model. Compared with a 2D monolayer culture, breast cancer MCF-7 cells residing in the HECS–GMA hydrogels grew as tumour-like clusters in a 3D formation. In a xenograft model, MCF-7 cells cultured in the HECS–GMA hydrogels had increased secretion of angiogenesis-related growth factors. Recombinant human endostatin (Endostar), but not Bevacizumab (Avastin), was an effective anti-angiogenic agent in HECS–GMA hydrogels.ConclusionsThe HECS–GMA hydrogel provided a 3D tumour model that mimicked the in vivo cancer microenvironment and supported the growth of MCF7 cells better than traditional tissue culture plates. The HECS–GMA hydrogel may offer an improved platform to minimize the gap between traditional tissue culture plates and clinical applicability. In addition, the anti-angiogenic efficacy of drugs such as Endostar and Bevacizumab can be more comprehensively studied and assessed in HECS–GMA hydrogels.

The effect of anti-angiogenic agents on overall survival in metastatic oesophago-gastric cancer: A systematic review and meta-analysis.

BackgroundStudies of anti-angiogenic agents (AAs), combined with chemotherapy (chemo) or as monotherapy in metastatic oesophago-gastric cancer (mOGC), have reported mixed outcomes. We undertook systematic review and meta-analysis to determine their overall benefits and harms.MethodsRandomized controlled trials in mOGC were sought investigating the addition of AAs to standard therapy (best supportive care or chemo). The primary endpoint was overall survival (OS) with secondary endpoints progression-free survival (PFS), overall response rate (ORR) and toxicity. Estimates of treatment effect from individual trials were combined using standard techniques. Subgroup analyses were performed by line of therapy, region, age, performance status, histological type, number of metastatic sites, primary site, mechanism of action and HER2 status.ResultsFifteen trials evaluating 3502 patients were included in quantitative analysis. The addition of AAs was associated with improved OS: HR 0·81 (95% CI 0·75–0·88, p<0·00001) and improved PFS: HR 0·68 (95% CI 0·63–0·74, p<0·00001). Subgroup analyses favoured greater benefit for OS in 2nd/3rd line settings (HR 0·74) compared to 1st-line settings (HR 0·91) (X2 = 6·00, p = 0·01). OS benefit was seen across all regions—Asia (HR 0·83) and rest of world (HR 0·75)—without significant subgroup interaction. Results from 8 trials evaluating 2602 patients were pooled for toxicity > = Grade 3: with OR 1·39 (95% CI 1·17–1·65).ConclusionsThe addition of AAs to standard therapy in mOGC improves OS. Improved efficacy was only observed in 2nd- or 3rd-line setting and not in 1st-line setting. Consistent OS benefit was present across all geographical regions. This benefit is at the expense of increased overall toxicity.

Abstract B14: The effect of sunitinib treatment in human melanoma xenografts: Associations with angiogenic profiles

Abstract The effect of antiangiogenic agents targeting the vascular endothelial growth factor A (VEGF-A) pathway has been reported to vary substantially in preclinical studies. Treatments with these agents have induced substantial reductions in vessel density in some tumor models, and minor or no reductions in vessel density in others. Additionally, the treatments have improved vascular function and oxygenation in some tumor models, and induced hypoxia in others. The purpose of this study was to investigate the effect of sunitinib treatment on the morphology and function of tumor vasculature in melanoma xenografts with different angiogenic profiles. A-07, U-25, D-12, and R-18 melanoma xenografts grown in dorsal window chambers were used as preclinical tumor models. Tumor-bearing mice were treated with sunitinib (40 mg/kg/day) or vehicle. Morphologic parameters of tumor vascular networks were assessed from high-resolution transillumination images, and tumor blood supply times were assessed from first-pass imaging movies recorded after a bolus of 155 kD tetramethylrhodamine isothiocyanate-labeled dextran was injected intravenously. Tumor hypoxia was assessed in immunohistochemical preparations by using pimonidazole as hypoxia marker, and the gene expression and the protein secretion rate of angiogenic factors were assessed by quantitative PCR and ELISA, respectively. The melanoma lines differed substantially in the expression of VEGF-A, VEGF-C, and platelet-derived growth factor A. Sunitinib treatment reduced vessel densities and induced hypoxia in all melanoma lines, and the magnitude of the effect was associated with the gene expression and protein secretion rate of VEGF-A. Sunitinib treatment also increased vessel segment lengths, reduced the number of small-diameter vessels, and inhibited growth-induced increases in the diameter of surviving vessels, but did not affect blood supply times. In conclusion, sunitinib treatment did not improve vascular function but reduced vessel density and induced hypoxia in human melanoma xenografts. The magnitude of the treatment-induced effect was associated with the angiogenic profiles of the melanoma lines. Citation Format: Jon-Vidar Gaustad, Trude G. Simonsen, Lise Mari K. Andersen, Einar K. Rofstad. The effect of sunitinib treatment in human melanoma xenografts: Associations with angiogenic profiles. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B14.

The novel kinase inhibitor ponatinib is an effective anti-angiogenic agent against neuroblastoma.

Background High-risk neuroblastoma has poor outcomes with high rates of relapse despite aggressive treatment, and novel therapies are needed to improve these outcomes. Ponatinib is a multi-tyrosine kinase inhibitor that targets many pathways implicated in neuroblastoma pathogenesis. We hypothesized that ponatinib would be effective against neuroblastoma in preclinical models. Methods We evaluated the effects of ponatinib on survival and migration of human neuroblastoma cells in vitro. Using orthotopic xenograft mouse models of human neuroblastoma, we analyzed tumors treated with ponatinib for growth, gross and histologic appearance, and vascularity. Results Ponatinib treatment of neuroblastoma cells resulted in decreased cell viability and migration in vitro. In mice with orthotopic xenograft neuroblastoma tumors, treatment with ponatinib resulted in decreased growth and vascularity. Conclusions Ponatinib reduces neuroblastoma cell viability in vitro and reduces tumor growth and vascularity in vivo. The antitumor effects of ponatinib suggest its potential as a novel therapeutic agent for neuroblastoma, and further preclinical testing is warranted.

Various miRNAs Predict Effect of Anti-Angiogenic Agents on Renal Cancer

Various miRNAs Predict Effect of Anti-Angiogenic Agents on Renal Cancer

Effect of regorafenib on angiogenesis in neuroendocrine tumors in vitro.

232 Background: Regorafenib, a potent multikinase inhibitor, targets a broad range of receptor tyrosine kinases (RTKs), including but not limited to VEGFR, PDGFR, and FGFR, which play an integral role in angiogenesis. Human neuroendocrine tumors (NETs) rely on RTKs to mediate tumor neovascularization, development, and metastasis. Similar kinase inhibitors like PTK787 profoundly inhibit angiogenesis in human NETs. We hypothesized that Regorafenib would have antiangiogenic and antitumor effect on human NETs. This study demonstrates inhibitory activity of Regorafenib on pathologic angiogenesis in vitro using our human tumor angiogenesis model (HTAM). Methods: Human NETs were collected in cell culture media in the O.R. and transported to the laboratory at 4⁰C. Tumors were minced into 2 mm fragments, embedded in a fibrin-thrombin clot and supplemented with a nutrient culture media. Neovessels were visually scored and evaluated based on three parameters: percent initiation, angiogenic growth, and overall angiogenic response. An effective concentration was selected for all successive HTAM assays based on dose response experiments. Angiogenesis data was obtained for 77 patients and analyzed for significance using paired samples t-test (MedCalc). Results: Dose-dependent inhibition of angiogenesis was observed for all NETs (n = 77): primary tumors (n = 11), lymph nodes (n = 28) and organ (n = 38) metastases. Selected dose of Regorafenib [1100 nM] achieved statistically significant inhibition of angiogenic growth (59%) and overall angiogenic response (44.5%) in all NETs (p &lt; 0.0001). However, there was no significant inhibition of percent initiation for all NETs except in primary tumors (p = 0.0260). Conclusions: Regorafenib is an effective antiangiogenic agent for NETs in-vitro. Regorafenib targets angiogenic growth in all NETs and inhibits initiation of angiogenesis exclusively in NET primary tumors. This suggests preferential use of Regorafenib for NET patients who have not yet developed metastases. Alternatively, Regorafenib could be an effective adjuvant treatment for advanced stage patients.

Beyond Bevacizumab: An Outlook to New Anti-Angiogenics for the Treatment of Ovarian Cancer.

In addition to the monoclonal vascular endothelial growth factor (VEGF) antibody bevacizumab, several alternative anti-angiogenic treatment strategies for ovarian cancer patients have been evaluated in clinical trials. Apart from targeting extracellular receptors by the antibody aflibercept or the peptibody trebananib, the multikinase inhibitors pazopanib, nintedanib, cediranib, sunitinib, and sorafenib were developed to interfere with VEGF receptors and multiple additional intracellular pathways. Nintedanib and pazopanib significantly improved progression-free survival in two positive phase III trials for first-line therapy. A reliable effect on overall survival could, however, not be observed for any anti-angiogenic first-line therapies so far. In terms of recurrent disease, two positive phase III trials revealed that trebananib and cediranib are effective anti-angiogenic agents for this indication. Patient selection and biomarker guided prediction of response seems to be a central aspect for future studies. Combining anti-angiogenics with other targeted therapies to possibly spare chemotherapy in certain constellations represents another very interesting future perspective for clinical trials. This short review gives an overview of current clinical trials for anti-angiogenic treatment strategies beyond bevacizumab. In this context, possible future perspectives combining anti-angiogenics with other targeted therapies and the need for specific biomarkers predicting response are elucidated.