A phase II evaluation of sunitinib in the treatment of persistent or recurrent clear cell ovarian carcinoma: An NRG Oncology/Gynecologic Oncology Group Study (GOG-254).

OBJECTIVES: To determine the efficacy and tolerability of sunitinib in recurrent or persistent clear cell ovarian cancer patients. METHODS: All patients had one or two prior regimens with measurable disease. Tumors were at least 50% clear cell histomorphology and negative for WT-1 antigen and estrogen receptor expression by immunohistochemistry. Sunitinib 50 mg per day for 4 weeks was administered in repeated 6-week cycles until disease progression or prohibitive toxicity. Primary end points were progression-free survival (PFS) at 6 months and clinical response. The study was designed to determine if the drug had a response rate of at least 20% or 6-month PFS of at least 25%. RESULTS: Of 35 patients enrolled, 30 were treated and eligible (median age: 51, range: 27-73). Twenty-five (83%) were White, 4 (13%) Asian, and 1 (3%) unknown. The majority 28 (83%) patients, underwent ≤3 but 2 (7%) had 16 courses of study therapy. Five (16.7%) patients had PFS ≥6 months (90% CI: 6.8%-31.9%). Two (6.7%) patients had a partial or complete response (90% CI: 1.2%-19.5%). The median PFS was 2.7 months. The median overall survival was 12.8 months. The most common grade 3 adverse events were fatigue (4), hypertension (4), neutropenia (4), anemia (3), abdominal pain (3), and leukopenia (3). Grade 4-5 adverse events included: thrombocytopenia (5), anemia (2), acute kidney Injury (1), stroke (1), and allergic reaction (1). CONCLUSION: Sunitinib demonstrated minimal activity in the second- and third-line treatment of persistent or recurrent clear cell ovarian carcinoma. ClinicalTrials.gov number, NCT00979992.

VEGF and SEMA4D have synergistic effects on the promotion of angiogenesis in epithelial ovarian cancer.

BACKGROUND: Anti-angiogenesis therapy that targets VEGF is one of the important treatment strategies in advanced ovarian cancer. However, depending on the pharmaceutical agent, treatment can have undesirable side effects. SEMA4D has recently gained interest for its role in promoting angiogenesis. Here, we try to further understand the mechanism by which SEMA4D promotes angiogenesis in ovarian cancer. METHODS: Correlation and western blot assaya were used to detect the relationship between VEGF and SEMA4D in clinical tissues and cells. Vasculogenic mimicry and transwell migration analyses were used to detect the roles of VEGF, SEMA4D and plexin-B1 on vasculogenic mimicry and migration. Vascular density and SEMA4D expression was determined using immunofluorescence staining in clinical tissues of EOC. Western blot was used to detect the expressions of CD31, MMP2 and VE-cadherin. We also analyzed the relationship between VEGF-SEMA4D and malignant tumor prognosis. RESULTS: We found that knockdown of VEGF could suppress SEMA4D expression and that the expressions of VEGF and SEMA4D have a positive correlation in EOC cancer tissues. Vasculogenic mimicry and transwell migration analyses showed that SEMA4D and VEGF have a synergistic effect on the promotion of angiogenesis in A2780 and HUVEC cells. Soluble SEMA4D (sSEMA4D) could promote VM and migration in A2780 and HUVEC cells via the SEMA4D/plexin-B1 pathway, but the effect was not noted in stably transfected shR-plexin-B1 cells. In clinical tissues of EOC, the vascular density and SEMA4D/plexin-B1 expression were higher. When VEGF, SEMA4D and plexin-B1 was knocked down, the expression of CD31, MMP2 and VE-cadherin, which are the markers and initiators of angiogenesis and the epithelial-mesenchymal transition (EMT) process were reduced. VEGF and SEMA4D had a positive correlation with the malignant degree of ovarian cancer, and SEMA4D can serve as an independent prognostic factor. CONCLUSIONS: VEGF and SEMA4D have synergistic effects on the promotion of angiogenesis in epithelial ovarian cancer. Targeting VEGF and the SEMA4D signaling pathway could be important for the therapy for EOC.

Inhibition effect of triptolide on human epithelial ovarian cancer via adjusting cellular immunity and angiogenesis.

Chemotherapy resistance of advanced ovarian cancers is responsible for death of most cancer patients, so it is necessary to seek safe and effective natural ingredients to lower the chemotherapy resistance of ovarian cancer. In the present study, we studied the anticancer effects of triptolide (TPL) and TPL + cisplatin (DDP) in vitro and in vivo using SKOV3/DDP cell line and a mouse model. In vitro results showed that TPL and TPL + DDP inhibited cellular invasion and migration of SKOV3/DDP cells (P<0.05), and significantly reduced the expression of adhesion-related proteins integrin ß1 (ITGß1) and apoptosis-inhibiting proteins survivin, matrix metalloproteinase 2 (MMP-2) and MMP-9 (P<0.05). Animal results demonstrated that TPL and TPL + DDP had significantly enhanced the inflammatory factor-2 (IL-2) and tumor necrosis factor-α (TNF-α) in serum of mice, and significantly increased the NK cell-related protein levels of CD16 and CD56, while significantly inhibited the production of vascular endothelial growth factor (VEGF) related protein clusters of differentiation 31 (CD31) and CD105. Collectively, the combination of TPL and DDP may produce a synergistic anticancer effect on epithelial ovarian cancer (EOC).

Crosstalk between TEMs and endothelial cells modulates angiogenesis and metastasis via IGF1-IGF1R signalling in epithelial ovarian cancer.

BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of death from gynaecologic malignancies and has a poor prognosis due to metastasis. Drugs targeting the angiogenesis pathway significantly improve patient outcome. However, the key factors linking angiogenesis and metastasis have not been elucidated. In this study, we found Tie2 expressing monocytes (CD14+Tie2+, TEMs) as key contributors to angiogenesis and metastasis of EOC. METHODS: Tissue slides were evaluated by immunofluorescence for the presence of total tissue macrophages and TEMs. The correlation between microvascular density (MVD) values and the TEMs number or ratio was calculated in both ovarian cancer tissues and peritoneum. The rate of TEMs in monocytes was evaluated in the peripheral blood of female healthy donors, benign cysts patients, and EOC patients using flow cytometry. The TEMs rate in ascites from EOC patients was also evaluated by flow cytometry. The concentration of Ang2, as the ligand of Tie2, was examined by ELISA in serum samples of EOC patients, benign cysts patients, and ascites samples of EOC patients. The effects of Ang2 on the migration and the cytokine expression of TEMs were further examined. The pro- angiogenesis activity of TEMs via IGF1 was performed in both in vivo and in vitro. And the IGF1 blocking test was performed using neutralising antibody. RESULTS: TEMs were significantly higher in tumour foci, peripheral blood and ascites in EOC patients. The proportion of TEMs among total tissue macrophages was positively correlated with tumour MVD. In vivo animal results showed that TEMs promoted EOC angiogenesis and metastasis. Further functional and mechanisms studies revealed that concentration of angiopoietin 2 (Ang2), a ligand of Tie2, was elevated in EOC ascites which further recruit TEMs in a dose-dependent manner as a powerful chemokine to TEMs. Recruited TEMs promoted endothelial cell function through IGF1-activated downstream signalling. Blocking secreted IGF1 using inhibiting antibody reduced TEMs mediated angiogenesis and metastasis. CONCLUSIONS: TEMs significantly increased in EOC patients and were recruited to tumour loci by the increased Ang2. The increased TEMs have diagnostic value in ovarian cancer and were positively correlated with the MVD in ovarian cancer tissue. Furthermore, TEMs promote angiogenesis via IGF1 in both in vivo and in vitro experimental systems after stimulation by Ang2. Altogether, this study paves the way to develop novel therapy targets as the axis of Ang2-TEMs-IGF1 in EOC.

Proliferation and maturation of intratumoral blood vessels in women with malignant ovarian tumors assessed with cancer stem cells marker nestin and platelet derived growth factor PDGF-B.

OBJECTIVES: Platelet-derived growth factor B (PDGF-B) and nestin have been suggested to be useful in the assessment of neoangiogenesis in malignant ovarian masses. We aimed to investigate a possible association of these markers with newly formed microcapillaries and perivascular cells in ovarian tumors. MATERIAL AND METHODS: Microvessel density (MVD) and pericytes were studied in 82 women with ovarian neoplasms, including 7 benign cysts, 7 borderline masses, 64 epithelial ovarian cancers and 4 other malignant ovarian tumors. Immunohistochemical staining included antibodies to CD34, PDGF-B and nestin. RESULTS: Median values of CD34-positive and nestin-positive MVD were: 24,5 (range:17-32) and 21 (range: 12-31), respectively. No significant correlation between intratumoral CD-34 positive MVD and nestin-positive MVD was found. Benign and borderline lesions more frequently than malignant tumors displayed low or medium values of nestin-positive MVD (p = 0.01). Histological grading of malignant tumors was associated with nestin-positive MVD (p = 0.01). Nestin expression in tumor cells was not correlated with tumor grade or histological subtype. PDGF-B expression was found in tumor microves-sels in 72% of cases (59/82). High expression of PDGF in pericapillary cells was strongly associated with high expression of this marker in cancer cells (p = 0.007). Significant correlations between PDGF-B and nestin expression in malignant tumor microvessels were also found (p = 0.04). Nestin and PDGF-B expressions were strongly associated with high grade tumors when compared to low grade or benign masses. CONCLUSIONS: We conclude that the assessment of PDGF-B and nestin-positive MVD could be used to identify only highly active, angiogenic malignant ovarian masses, where tumor vasculature is formed.

Potential Coagulation Factor-Driven Pro-Inflammatory Responses in Ovarian Cancer Tissues Associated with Insufficient O2 and Plasma Supply.

Tissue factor (TF) is a cell surface receptor for coagulation factor VII (fVII). The TF-activated fVII (fVIIa) complex is an essential initiator of the extrinsic blood coagulation process. Interactions between cancer cells and immune cells via coagulation factors and adhesion molecules can promote progression of cancer, including epithelial ovarian cancer (EOC). This process is not necessarily advantageous, as tumor tissues generally undergo hypoxia due to aberrant vasculature, followed by reduced access to plasma components such as coagulation factors. However, hypoxia can activate TF expression. Expression of fVII, intercellular adhesion molecule-1 (ICAM-1), and multiple pro-inflammatory cytokines can be synergistically induced in EOC cells in response to hypoxia along with serum deprivation. Thus, pro-inflammatory responses associated with the TF-fVIIa-ICAM-1 interaction are expected within hypoxic tissues. Tumor tissue consists of multiple components such as stromal cells, interstitial fluid, albumin, and other micro-factors such as proton and metal ions. These factors, together with metabolism reprogramming in response to hypoxia and followed by functional modification of TF, may contribute to coagulation factor-driven inflammatory responses in EOC tissues. The aim of this review was to describe potential coagulation factor-driven inflammatory responses in hypoxic EOC tissues. Arguments were extended to clinical issues targeting this characteristic tumor environment.

Adrenomedullin promotes angiogenesis in epithelial ovarian cancer through upregulating hypoxia-inducible factor-1α and vascular endothelial growth factor.

Adrenomedullin (ADM) is a multi-functional peptide related to many kinds of tumors. This study was aimed to investigate the role of ADM on angiogenesis in epithelial ovarian cancer (EOC) and its possible mechanism. The expressions of ADM, vascular endothelial growth factor (VEGF), hypoxia-inducible factor-1α (HIF-1α) and CD34 were examined by immunohistochemistry staining. The relationship among ADM, HIF-1α, VEGF and micro-vessel density (MVD) was assessed in 56 EOC tissues. CAOV3 cells were stably transfected with pcDNA-ADM (plasmid overexpressing ADM gene) or pRNA-shADM (small interfering RNA for ADM gene). Real-time PCR and western blot analysis were performed to detect the expressions of HIF-1α and VEGF. The MTT, transwell migration assay and in vitro tube formation analysis were used to evaluate the proliferation, migration, and tube formation ability of human umbilical vein endothelial cells (HUVECs) which were pretreated with ADM or ADM receptor antagonist ADM22-52. Our findings showed that ADM expression was positively correlated with the expressions of HIF-1α, VEGF or MVD in EOC. ADM upregulated expression of HIF-1α and VEGF in CAOV3 cells. ADM promoted HUVECs proliferation, migration and tube formation. In conclusion, ADM was an upstream molecule of HIF-1α/VEGF and it promoted angiogenesis through upregulating HIF-1α/VEGF in EOC.

Emerging Role of Nestin as an Angiogenesis and Cancer Stem Cell Marker in Epithelial Ovarian Cancer: Immunohistochemical Study.

Ovarian cancer is the most fatal gynecologic malignancy and the existing second-line treatments have not been confirmed to be effective. Cancer stem cells research has a leading role to explore promising therapeutic applications. Nestin was postulated to reflect cancer stem cell properties in various tumors, correlating with poor prognosis. Furthermore, nestin is proposed as a reliable neovascularization marker. This study aimed to elucidate the status of nestin expression in various epithelial ovarian cancers (EOCs), its neoangiogenic properties, and investigate its potential association with clinicopathologic parameters. A total of 80 primary EOCs (37 serous, 20 Mucinous, 13 endometrioid, and 10 clear cell carcinomas) were immunohistochemically stained with nestin. Staining intensity and automated microvascular density (MVD) were assessed. Positive nestin expression was defined in ≈47.5% of all EOC; more commonly in ≈60% of the serous tumors. It was noticeably expressed in tumor spheroids. Nestin expression significantly correlated with overall tumor grade, lymph node, distant metastasis, and stage. Nestin neoangiogenesis was detectable in all cases (average=60.1). The nestin expression in tumor cells significantly correlated with Nestin/MVD. The average Nestin/MVD was significantly an independent predictor of high tumor stage. As a stem cell marker, nestin is expressed in cells of EOC including those growing as spherules and correlated with poor prognosis. Thus, nestin may be a novel therapeutic target for tumor angiogenesis and a combination therapy that includes nestin-targeting agents may be an effective therapeutic approach. In addition, detection of Nestin/stem cells and Nestin/MVD can be used as predictors of disease.

Expression of a novel endothelial marker, C-type lectin 14A, in epithelial ovarian cancer and its prognostic significance.

OBJECTIVE: The purpose of this study was to evaluate microvessel density (MVD) as assessed by C-type lectin 14A (CLEC14A), which is a new marker for endothelial cells, and compare its expression to CD31 and CD105 in epithelial ovarian cancer (EOC). METHODS: MVD was evaluated in tumors (n = 50) from patients with EOC who underwent primary surgery and in patients with EOC who received preoperative chemotherapy (n = 49) using immunohistochemistry with antibodies to CLEC14A, CD31 and CD105. The median duration of follow-up was 24.5 months (range 1-101 months). The effect of prognostic factors on event-free survival (EFS) and overall survival (OS) was assessed using the Cox regression model. RESULTS: The amount of residual disease was found to be an independent prognostic factor in multivariate analysis with respect to EFS (P = 0.009) and OS (P < 0.001). The mean MVD of CLEC14A (MVD = 6), in tumors from patients who underwent primary surgery, was significantly lower than that of CD31 (MVD = 25, P < 0.0001) and CD105 (MVD = 11, P = 0.018). However, there was no significant correlation between MVD as detected by these markers and clinical outcome. There was no expression of CLEC14A in tumors from patients who received preoperative chemotherapy and the MVD of CD31 and CD105 was significantly reduced (P = 0.001 and 0.006, respectively) in this set of patients. CONCLUSION: This study demonstrates MVD as detected by CLEC14A in EOC. Treatment with chemotherapy reduces tumor blood vessels significantly. We suggest that CLEC14A may be a more specific endothelial marker to assess tumor angiogenesis.

The associations between serum VEGF, bFGF and endoglin levels with microvessel density and expression of proangiogenic factors in malignant and benign ovarian tumors.

AIM OF THE STUDY: To investigate whether serum levels of VEGF, bFGF and endoglin correlate with tumor VEGF and bFGF expression or microvessel density (MVD) in ovarian cancer. PATIENTS AND METHODS: Forty five patients with epithelial ovarian cancers (EOCs) and 38 patients with benign ovarian tumors (BOTs) were included into the study. Serum levels of VEGF, bFGF and endoglin were assessed using ELISA. The expression of VEGF and bFGF in tumor samples were evaluated using ELISA of supernatants obtained from tumor homogenization. MVD was analyzed using immunohistochemistry with antibodies against CD31, CD34 and CD105. RESULTS: Serum VEGF levels were significantly higher in EOCs than in BOTs (436.6pg/ml [19.67-2860] vs 295.5pg/ml [123-539], P=0.025). Serum endoglin levels were lowered in the group EOCs when compared to BOTs (33,720g/ml [12,220-73,940] vs 42,390pg/ml [19,380-56,910], P=0.015). There were no differences in bFGF levels between studied groups. EOCs have significantly higher CD105 MVD (25 vessels/mm2 [0-57] vs 6 vessels/mm2 [0-70], P<0.001) and tumor VEGF (405.9pg/mg protein [0-3000] vs 2.225 [0-634.7], P<0.001) expression than BOTs, while, bFGF expression was higher in BOTs than in EOCs (2076pg/mg protein [668.1-8718] vs 847.3pg/mg protein [188.9-8333], P=0.003). In patients with EOCs we have observed negative correlation between serum VEGF concentration and its tissue expression (r Spearman=-0.571, P=0.0261), and serum VEGF concentration correlated positively with CD34-MVD (r Spearman=0.545, P=0.0289). In a multiple regression analysis we have observed only the negative correlation between serum VEGF and CD105-MVD (r=-0.5288, P=0.0427). CONCLUSIONS: Serum VEGF is a useful marker for prediction of ovarian cancer MVD and tumor VEGF expression.

Fibroblast recruitment as a tool for ovarian cancer detection and targeted therapy.

Metastatic ovarian cancer, the most lethal of gynecologic malignancies, is typically managed by debulking surgery, followed by chemotherapy. However, despite significant efforts, survival rate remains low. We have previously demonstrated, in mouse models, a specific systemic homing of labeled fibroblasts to solid ovarian tumors. Here, we demonstrate the feasibility of utilizing this specific homing of genetically modified fibroblasts for detection and targeted therapy of orthotopic metastatic ovarian carcinoma model in immune-deficient mice. Using an in vivo metastatic mouse model for ovarian cancer, we demonstrated that fibroblasts expressing fluorescent reporters injected intra-peritoneally, were specifically recruited to peritoneal tumor nodules (resulting in 93-100% co-localization). We further used fibroblasts over expressing the soluble receptor variant of VEGFR1 (s-Flt1). Mice bearing tumors were injected weekly with either control or s-Flt1 expressing fibroblasts. Injection of s-Flt1 expressing fibroblasts resulted in a significant reduction in the ascites volume, reduced vascularization of adherent metastases, and improved overall survival. Using fluorescently labeled fibroblasts for tumor detection with readily available intra-operative fluorescence imaging tools may be useful for tumor staging and directing biopsies or surgical efforts during exploratory or debulking surgery. Fibroblasts may serve as a beacon pointing to the otherwise invisible metastases in the peritoneal cavity of ovarian cancer patients. Utilizing the recruited fibroblasts also for targeted delivery of anti angiogenic or antitumor molecules may aid in controlling tumor progression. Thus, these results suggest a novel approach for targeting ovarian tumor metastases for both tumor detection and therapy.

Migration-inducing gene 7 promotes tumorigenesis and angiogenesis and independently predicts poor prognosis of epithelial ovarian cancer.

Epithelial ovarian carcinomas (EOC) cause more mortality than any other cancer of the female reproductive system. New therapeutic approaches to reduce EOC mortality have been largely unsuccessful due to the poor understanding of the mechanisms underlying EOC proliferation and metastasis. Progress in EOC treatment is further hampered by a lack of reliable prognostic biomarkers for early risk assessment. In this study, we identify that Migration-Inducting Gene 7 (MIG-7) is specifically induced in human EOC tissues but not normal ovaries or ovarian cyst. Ovarian MIG-7 expression strongly correlated with EOC progression. Elevated MIG-7 level at the time of primary cytoreductive surgery was a strong and independent predictor of poor survival of EOC patients. Cell and murine xenograft models showed that MIG-7 was required for EOC proliferation and invasion, and MIG-7 enhanced EOC-associated angiogenesis by promoting the expression of vascular endothelial growth factor. Inhibiting MIG-7 by RNA interference in grafted EOC cells retarded tumor growth, angiogenesis and improved host survival, and suppressing MIG-7 expression with a small molecule inhibitor D-39 identified from the medicinal plant Liriope muscari mitigated EOC growth and invasion and specifically abrogated the expression of vascular endothelial growth factor. Our data not only reveal a critical function of MIG-7 in EOC growth and metastasis and support MIG-7 as an independent prognostic biomarker for EOC, but also demonstrate that therapeutic targeting of MIG-7 is likely beneficial in the treatment of EOC.

Efficacy of trebananib (AMG 386) in treating epithelial ovarian cancer.

INTRODUCTION: Epithelial ovarian cancer (EOC) is the leading cause of death among gynecologic cancers. The majority of women are diagnosed with advanced stage disease. It is considered a chemosensitive cancer with a high initial response rate to first-line platinum and taxane-based chemotherapy. However, most patients with advanced EOC will relapse with subsequent resistance to conventional chemotherapy and ultimately succumb to their disease. Therefore, new therapeutic agents and strategies are desperately needed to improve the outcomes in patients with advanced EOC. AREAS COVERED: This review focuses on the use of Trebananib (a non-VEGF-dependent angiogenesis pathway inhibitor) in EOC. Angiogenesis has been recognized as an important process promoting EOC growth and metastasis. Targeting angiogenesis in EOC have been developed and studied with demonstrated clinical efficacy. Bevacizumab, a humanized monoclonal antibody, that targets vascular endothelial growth factor A (VEGF-A), has been the most well evaluated molecular targeted therapy in the treatment of advanced and recurrent EOC with proven clinical efficacy. However, VEGF-dependent angiogenesis pathway inhibitors are often associated with serious toxicities and drug resistance ultimately develops. Hence, new therapeutic approach targeting the angiopoietin-Tie-2 complex pathway (a non-VEGF-dependent angiogenesis pathway) has gained interest over the past few years as an alternative strategy to overcome VEGF-dependent anti-angiogenesis-related toxicity and resistance. EXPERT OPINION: Targeting angiopoietin-Tie-2 pathway represents a promising alternative approach to tumor anti-angiogenesis with a distinct toxicity profile from the VEGF-dependent pathway inhibitors. However, there are still many questions to be answered regarding the optimal treatment schedules, maintenance regimens, duration of maintenance therapy, and the best combination strategy. Currently there is no reliable surrogate molecular, cellular, or genetic marker that would definitively predict response to anti-angiogenic therapy. Identification of certain relevant and predictive biomarkers in the future may optimize treatment's efficacy by distinguishing the subset group of patients with EOC that would derive the most benefit from existing antiangiogenic treatment regimens.

Targeting the tumour microenvironment in ovarian cancer.

The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells, and the view that they proliferate due to uncontrolled growth signalling owing to genetic derangements. However, uncontrolled growth in tumours cannot be explained solely by aberrations in cancer cells themselves. To fully understand the biological behaviour of tumours, it is essential to understand the microenvironment in which cancer cells exist, and how they manipulate the surrounding stroma to promote the malignant phenotype. Ovarian cancer is the leading cause of death from gynaecologic cancer worldwide. The majority of patients will have objective responses to standard tumour debulking surgery and platinum-taxane doublet chemotherapy, but most will experience disease recurrence and chemotherapy resistance. As such, a great deal of effort has been put forth to develop therapies that target the tumour microenvironment in ovarian cancer. Herein, we review the key components of the tumour microenvironment as they pertain to this disease, outline targeting opportunities and supporting evidence thus far, and discuss resistance to therapy.

High-grade ovarian cancer secreting effective exosomes in tumor angiogenesis.

Ovarian cancer, the most lethal gynecological cancer, related closely to tumor stage. High-grade ovarian cancer always results in a late diagnose and high recurrence, which reduce survival within five years. Until recently, curable therapy is still under research and anti-angiogenesis proves a promising way. Tumor-derived exosomes are essential in tumor migration and metastases such as angiogenesis is enhanced by exosomes. In our study, we have made comparison between high-grade and unlikely high-grade serous ovarian cancer cells on exosomal function of endothelial cells proliferation, migration and tube formation. Exosomes derived from high-grade ovarian cancer have a profound impact on angiogenesis with comparison to unlikely high-grade ovarian cancer. Proteomic profiles revealed some potential proteins involved in exosomal function of angiogenesis such as ATF2, MTA1, ROCK1/2 and so on. Therefore, exosomes plays an influential role in angiogenesis in ovarian serous cancer and also function more effectively in high-grade ovarian cancer cells.

Emerging therapies: angiogenesis inhibitors for ovarian cancer.

INTRODUCTION: Patients with epithelial ovarian cancer (EOC) have a high rate of recurrence, and overall survival remains at ∼ 25%. There is a need for new treatments that can increase progression free survival and quality of life. Recent clinical trials focus on angiogenesis, VEGFs, and tyrosine kinase inhibitors that play a role in recurrence, metastasis, and ascites in EOC. AREAS COVERED: This review summarizes clinical rationale, mechanisms of action, and clinical data for angiogenesis inhibitors under evaluation in Phase II and III trials for EOC. Anti-angiogenesis agents reviewed in this paper include aflibercept, bevacizumab, cediranib, fosbretabulin, imatinib, nintedanib, pazopanib, saracatinib, sorafenib, sunitinib, and trebananib. EXPERT OPINION: These agents have particular rationale for potential use in EOC due to the molecular changes associated with EOC tumorigenesis, namely a significant increase in angiogenic activity. Due to the costs and toxicities associated with anti-angiogenics, biomarker or molecular signature selection strategy for patients who will most benefit would be ideal but no such strategy has been validated to date.

The search for biomarkers to direct antiangiogenic treatment in epithelial ovarian cancer.

Antiangiogenic agents have demonstrated improved progression-free survival in women with primary and recurrent epithelial ovarian cancer (EOC). Biomarkers that predict outcomes in patients treated with antiangiogenic agents are being investigated to rationally direct therapy for women most likely to benefit from these agents. Among the most promising plasma-based biomarkers are vascular endothelial growth factor (VEGF)-A, fibroblast growth factor, platelet-derived growth factor, angiopoietin-2, and VEGF receptor-2. While these biomarkers have been correlated with prognosis, they have not been shown to predict benefit, specifically from anti-VEGF therapy, highlighting the need for alternative biomarkers, including molecular and clinical factors, which may be predictive of outcome in women with ovarian cancer treated with antiangiogenic agents. Biomarkers are currently being investigated as secondary outcomes in several ongoing phase II and phase III clinical trials of antiangiogenic agents in patients with EOC. Molecular techniques, such as microarray analyses, and imaging techniques, such as dynamic contrast-enhanced magnetic resonance imaging, positron emission tomography, and single photon emission computed tomography, are also being explored in this field. In this review, we provide a comprehensive overview of current biomarker research, with an emphasis on angiogenic biomarkers associated with EOC.

[Maintenance therapy in patients with advanced epithelial ovarian cancer-impact of anti-angiogenic molecular targeted agents in progress].

However, in patients with epithelial ovarian cancer, the standard chemotherapy of paclitaxel/carboplatin (TC) therapy is very effective as the overall survival (OS) reached 70-80% in early stage (stage I/II ) patients, in advanced stage patients like stage III/IV the recurrence rate exceeds 80%and the 5-year-OS remains 55%at most. Longer survival remains so worse as well that the 10-year-OS fails to 5-7%. In order to push up the rate of longer survival, the strategies have been considered from the some points of view such as additional new anti-cancer agents, changing of drug delivery system (DDS) (i.e. intraperitoneal administration), additional radiotherapy or radioactive agents (in USA), the combination of molecular agents and specific classification in treatment using "Bio-markers (so-called tailor-made medicine)". Here we reviewed the up-coming treatments in maintenance fashion using anti-angiogenic agents or supposing effective and curable treatment by PARP inhibitors in the cohorts of epithelial ovarian cancers with BRCAness.

Focal adhesion kinase: an alternative focus for anti-angiogenesis therapy in ovarian cancer.

This investigation describes the clinical significance of phosphorylated focal adhesion kinase (FAK) at the major activating tyrosine site (Y397) in epithelial ovarian cancer (EOC) cells and tumor-associated endothelial cells. FAK gene amplification as a mechanism for FAK overexpression and the effects of FAK tyrosine kinase inhibitor VS-6062 on tumor growth, metastasis, and angiogenesis were examined. FAK and phospho-FAK(Y397) were quantified in tumor (FAK-T; pFAK-T) and tumor-associated endothelial (FAK-endo; pFAK-endo) cell compartments of EOCs using immunostaining and qRT-PCR. Associations between expression levels and clinical variables were evaluated. Data from The Cancer Genome Atlas were used to correlate FAK gene copy number and expression levels in EOC specimens. The in vitro and in vivo effects of VS-6062 were assayed in preclinical models. FAK-T and pFAK-T overexpression was significantly associated with advanced stage disease and increased microvessel density (MVD). High MVD was observed in tumors with elevated endothelial cell FAK (59%) and pFAK (44%). Survival was adversely affected by FAK-T overexpression (3.03 vs 2.06 y, P = 0.004), pFAK-T (2.83 vs 1.78 y, P<0.001), and pFAK-endo (2.33 vs 2.17 y, P = 0.005). FAK gene copy number was increased in 34% of tumors and correlated with expression levels (P<0.001). VS-6062 significantly blocked EOC and endothelial cell migration as well as endothelial cell tube formation in vitro. VS-6062 reduced mean tumor weight by 56% (P = 0.005), tumor MVD by 40% (P = 0.0001), and extraovarian metastasis (P<0.01) in orthotopic EOC mouse models. FAK may be a unique therapeutic target in EOC given the dual anti-angiogenic and anti-metastatic potential of FAK inhibitors.