Anti-angiogenic therapy for cancer: Current progress, unresolved questions and future directions

Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies. © 2014 The Author(s)

TIMP-1 and VEGF-165 serum concentration during first-line therapy of ovarian cancer patients

<p>Abstract</p> <p>Background</p> <p>Angiogenesis appears to play an important role in ovarian cancer. Vascular endothelial growth factor (VEGF) has recently been implicated as a therapeutic target in ovarian cancer. The tissue inhibitor of metalloproteinase 1 (TIMP-1) is involved in tissue invasion and angiogenesis. The application of serum TIMP-1 and VEGF to monitor primary therapy and predict clinical outcome of patients with ovarian cancer is unclear.</p> <p>Methods</p> <p>Patients with epithelial ovarian cancer who presented for primary surgery were included in this study. A total of 148 serum samples from 37 patients were analyzed. Samples were prospectively collected at 4 predefined time points: 1. before radical debulking surgery, 2. after surgery and before platinum/taxane based chemotherapy, 3. during chemotherapy, 4. after chemotherapy. Serum VEGF-165 and TIMP-1 as well as CA-125 were quantified by ELISA or ECLIA and correlation with response and long-term clinical outcome was analyzed.</p> <p>Results</p> <p>Serum levels of all markers changed substantially during first-line therapy. High CA-125 (p = 0.002), TIMP-1 (p = 0.007) and VEGF-165 (p = 0.02) after chemotherapy were associated with reduced overall survival. In addition, elevated CA-125 (p < 0.001) and VEGF-165 (p = 0.006) at this time point predicted poor progression-free survival. TIMP-1 and VEGF-165 were closely correlated at all time-points during therapy.</p> <p>Conclusions</p> <p>TIMP-1 and VEGF serum levels changed significantly during first-line therapy of ovarian cancer patients and predicted prognosis. These findings support the role of angiogenesis in ovarian cancer progression and the use of antiangiogenic therapy.</p

Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer

Vascular endothelial growth factor (VEGF) is a key regulator of angiogenesis which drives endothelial cell survival, proliferation, and migration while increasing vascular permeability. Playing an important role in the physiology of normal ovaries, VEGF has also been implicated in the pathogenesis of ovarian cancer. Essentially by promoting tumor angiogenesis and enhancing vascular permeability, VEGF contributes to the development of peritoneal carcinomatosis associated with malignant ascites formation, the characteristic feature of advanced ovarian cancer at diagnosis. In both experimental and clinical studies, VEGF levels have been inversely correlated with survival. Moreover, VEGF inhibition has been shown to inhibit tumor growth and ascites production and to suppress tumor invasion and metastasis. These findings have laid the basis for the clinical evaluation of agents targeting VEGF signaling pathway in patients with ovarian cancer. In this review, we will focus on VEGF involvement in the pathophysiology of ovarian cancer and its contribution to the disease progression and dissemination

Hsp90 Inhibitors Are Efficacious against Kaposi Sarcoma by Enhancing the Degradation of the Essential Viral Gene LANA, of the Viral Co-Receptor EphA2 as well as Other Client Proteins

Heat-shock protein 90 (Hsp90) inhibitors exhibit activity against human cancers. We evaluated a series of new, oral bioavailable, chemically diverse Hsp90 inhibitors (PU-H71, AUY922, BIIB021, NVP-BEP800) against Kaposi sarcoma (KS). All Hsp90 inhibitors exhibited nanomolar EC(50) in culture and AUY922 reduced tumor burden in a xenograft model of KS. KS is associated with KS-associated herpesvirus (KSHV). We identified the viral latency associated nuclear antigen (LANA) as a novel client protein of Hsp90 and demonstrate that the Hsp90 inhibitors diminish the level of LANA through proteasomal degradation. These Hsp90 inhibitors also downregulated EphA2 and ephrin-B2 protein levels. LANA is essential for viral maintenance and EphA2 has recently been shown to facilitate KSHV infection; which in turn feeds latent persistence. Further, both molecules are required for KS tumor formation and both were downregulated in response to Hsp90 inhibitors. This provides a rationale for clinical testing of Hsp90 inhibitors in KSHV-associated cancers and in the eradication of latent KSHV reservoirs