Vascular endothelial growth factor (VEGF) pathway as a therapeutic target in gynecologic malignancies

Frumovitz, Michael; Sood, Anil K.

doi:10.1016/j.ygyno.2006.10.062

Cited by 60 publications

(40 citation statements)

References 76 publications

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“…Targeting the VEGF pathway has provided promising proof that antiangiogenic therapies can indeed improve therapeutic outcomes among cancer patients (37). Initial clinical trials with bevacizumab in ovarian cancer have shown encouraging results (38,39). However, it is likely that additional targets may be required to achieve further gains in patient survival.…”

Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacy of a Novel Focal Adhesion Kinase Inhibitor TAE226 in Ovarian Carcinoma

et al. 2007

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Focal adhesion kinase (FAK) overexpression is frequently found in ovarian and other cancers and is predictive of poor clinical outcome. In the current study, we characterized the biological and therapeutic effects of a novel FAK inhibitor, TAE226. Taxane-sensitive (SKOV3ip1 and HeyA8) and taxaneresistant (HeyA8-MDR) cell lines were used for in vitro and in vivo therapy experiments using TAE226 alone and in combination with docetaxel. Assessment of cytotoxicity, cell proliferation [proliferating cell nuclear antigen (PCNA)], angiogenesis (CD31), and apoptosis (terminal nucleotidyl transferase-mediated nick end labeling) were done by immunohistochemistry and immunofluorescence. In vitro, TAE226 inhibited the phosphorylation of FAK at both Y397 and Y861 sites, inhibited cell growth in a time-and dosedependent manner, and enhanced docetaxel-mediated growth inhibition by 10-and 20-fold in the taxane-sensitive and taxane-resistant cell lines, respectively. In vivo, FAK inhibition by TAE226 significantly reduced tumor burden in the HeyA8, SKOV3ip1, and HeyA8-MDR models (46-64%) compared with vehicle-treated controls. However, the greatest efficacy was observed with concomitant administration of TAE226 and docetaxel in all three models (85-97% reduction, all P values <0.01). In addition, TAE226 alone and in combination with chemotherapy significantly prolonged survival in tumorbearing mice. Even in larger tumors, combination therapy with TAE226 and docetaxel resulted in tumor regression. The therapeutic efficacy was related to reduced pericyte coverage, induction of apoptosis of tumor-associated endothelial cells, and reduced microvessel density and tumor cell proliferation. The novel FAK inhibitor, TAE226, offers an attractive therapeutic approach in ovarian carcinoma. [Cancer Res 2007;67(22):10976-83]

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Section: Discussionmentioning

confidence: 99%

Therapeutic Efficacy of a Novel Focal Adhesion Kinase Inhibitor TAE226 in Ovarian Carcinoma

et al. 2007

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“…When the balance is broken in favour of positive regulators, the switch of the angiogenesis malignant tumour phenotype is activated within a complex scenario, in which tumour cells, local blood vessels, angiogenesis-stimulating and -inhibiting factors and various components of the extracellular matrix play a role. This angiogenesis switch is triggered by microenvironmental conditions activating the process, mainly tissular hypoxia and cytokine release [3].…”

Section: Angiogenesis and Ovarian Cancermentioning

confidence: 99%

Current status of anti-angiogenic agents in the treatment of ovarian carcinoma

et al. 2009

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During the last decade we have assisted in the development of new therapeutic strategies for the treatment of ovarian cancer, based on the best knowledge of molecular biology. One of the most promising strategies under investigation is antiangiogenic therapy. Bevacizumab is a monoclonal humanised antibody targeting vascular endothelial growth factor (VEGF), which has shown antitumour activity in ovarian cancer in preclinical models as well as in clinical trials, both in monotherapy and in combination with other therapies. Currently, ongoing phase III trials are testing bevacizumab as a front-line therapy with carboplatin and paclitaxel. Bevacizumab has been generally well tolerated with mild frequent toxicities (proteinuria, hypertension and bleeding). However, the drug may result in other uncommon, but potentially life-threatening side effects, such as arterial thromboembolism, wound healing complications, and gastrointestinal perforation or fistulae, which should be considered when the drug is administered. Other new therapeutic antiangiogenic strategies that include small-molecule tyrosine kinase inhibitors, antibodies neutralising the VEGF receptor (VEGFR) and soluble VEGFR hybrids (VEGF Trap) are being investigated with promising early results.

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“…One study analyzed WA's potential for molecular docking through programs such as SwissDock and Docking Server [70]. Current anti-angiogenic therapies approved by the FDA, such as Bevacizumab, have serious to life-threatening side effects, and have little effect on brain tumor invasiveness [71][72][73]. After treatment with Bevacizumab, glioblastomas will adapt by upregulating glycolysis production, moving towards a more anaerobic metabolism, and inducing a microenvironmental acidosis.…”

Section: Effects On Angiogenesismentioning

confidence: 99%

Treatment of adult and pediatric high-grade gliomas with Withaferin A: antitumor mechanisms and future perspectives

et al. 2016

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Resistance mechanisms employed by high-grade gliomas allow them to successfully evade current standard treatment of chemotherapy and radiation treatment. Withaferin A (WA), utilized in Ayurvedic medicine for centuries, is attracting attention for its antitumor capabilities. Here we review pertinent literature on WA as a high-grade glioma treatment, and discuss the cancerous mechanisms it affects. WA is relatively nontoxic and has shown potential in crossing the blood-brain barrier. WA prevents p53 alterations and inactivates overexpressed MDM2 through ARF and ROS production. Furthermore, WA upregulates Bax, inducing mitochondrial death cascades, inhibits mutated Akt, mTOR, and NF-κB pathways, and inhibits angiogenesis in tumors. Therapy with WA for high-grade gliomas is supported through the literature. Further investigation is warranted and encouraged to fully unearth its abilities against malignant gliomas.

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Vascular endothelial growth factor (VEGF) pathway as a therapeutic target in gynecologic malignancies

Cited by 60 publications

References 76 publications

Therapeutic Efficacy of a Novel Focal Adhesion Kinase Inhibitor TAE226 in Ovarian Carcinoma

Therapeutic Efficacy of a Novel Focal Adhesion Kinase Inhibitor TAE226 in Ovarian Carcinoma

Current status of anti-angiogenic agents in the treatment of ovarian carcinoma

Treatment of adult and pediatric high-grade gliomas with Withaferin A: antitumor mechanisms and future perspectives

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