Antiangiogenic Therapy In Ovarian Cancer Research Articles

Anti-angiogenic therapy in ovarian cancer: Current understandings and prospects of precision medicine.

Ovarian cancer (OC) remains the most fatal disease of gynecologic malignant tumors. Angiogenesis refers to the development of new vessels from pre-existing ones, which is responsible for supplying nutrients and removing metabolic waste. Although not yet completely understood, tumor vascularization is orchestrated by multiple secreted factors and signaling pathways. The most central proangiogenic signal, vascular endothelial growth factor (VEGF)/VEGFR signaling, is also the primary target of initial clinical anti-angiogenic effort. However, the efficiency of therapy has so far been modest due to the low response rate and rapidly emerging acquiring resistance. This review focused on the current understanding of the in-depth mechanisms of tumor angiogenesis, together with the newest reports of clinical trial outcomes and resistance mechanism of anti-angiogenic agents in OC. We also emphatically summarized and analyzed previously reported biomarkers and predictive models to describe the prospect of precision therapy of anti-angiogenic drugs in OC.

Anti-angiogenic therapy in ovarian cancer: current situation & prospects.

Ovarian cancer (OC) is one of five leading causes of cancer related death among women worldwide. Although treatment has been improving, the survival rate has barely improved over the past 30 years. The fatality rate is due to asymptomatic early signs and the lack of long-term effective treatment strategies for advanced disease. Angiogenesis is an important process in tumour growth and metastasis and is the creation of new blood vessels from existing blood vessels. It is a dynamic and complex process involving various molecular regulatory pathways and multiple mechanisms. The inhibition of angiogenesis has become a recognized therapeutic strategy for many solid tumours. While benefits in progression-free survival have been observed, the OS is far from satisfactory for OC patients who receive antiangiogenic therapy. In this article, the present research status of angiogenesis in OC was reviewed and the reasons for poor antiangiogenic therapeutic effects was explored with the aim to identify potential therapeutic targets that may improve the effect of antiangiogenic therapies.

Abstract 1048: Genomic analysis of patients with relapsed ovarian cancer enrolled in a phase II trial of nivolumab and bevacizumab

Abstract We analyzed genomic alterations in patients with relapsed ovarian cancer treated with combined nivolumab and bevacizumab in a phase II clinical trial, in order to identify potential biomarkers of response. Thirty-eight patients were treated with nivolumab and bevacizumab and the previously reported overall response rate was 28.9% (Liu et al, JAMA Oncology, 2019). Formalin-fixed paraffin-embedded patient tumor samples (acquired pre-treatment) underwent whole-exome sequencing, followed by quality control filtering and analysis of mutations, insertions/deletions, copy-number alterations, and mutational signatures using established methods. Differences in genomic event rates were assessed between response groups, as defined by presence or absence of objective response or clinical benefit. We describe the genomic alterations in all patients treated with nivolumab and bevacizumab, including several long-term responders with treatment duration >24 months. The observed alterations in the patient cohort reflected known patterns of common mutations (e.g. TP53) and copy-number alterations (e.g. MYC amplification) in ovarian cancer. Within the limits of sample size, no significant differences in frequency of specific mutations were observed between response groups, with the possible exception of mutations in SETD1B, a histone methyltransferase, which were more frequent in the subset of patients lacking clinical benefit. BRCA1/2 mutation rate was similar between groups. Tumor mutational burden was not significantly different between groups. Initial exploratory analysis for copy-number alterations did not reveal genes with differential copy-number alterations between the response groups, and further analyses of copy-number alterations and mutational signatures are in progress. In summary, we describe genomic biomarker analysis from tumors of patients with relapsed ovarian cancer receiving treatment with nivolumab and bevacizumab. Taken together, we did not identify genomic alterations that clearly distinguish responding and non-responding patients in the data evaluated to date. Analysis of targeted RNA-sequencing data is planned as a next step. Further studies are needed to identify genomic or transcriptomic biomarkers of responses to checkpoint blockade and anti-angiogenic therapy in ovarian cancer. Citation Format: Elizabeth H. Stover, Svitlana Tyekucheva, Yiwen Liu, Jennifer D. Curtis, Richard T. Penson, Joyce F. Liu. Genomic analysis of patients with relapsed ovarian cancer enrolled in a phase II trial of nivolumab and bevacizumab [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1048.

Abstract AP21: A NOVEL TARGET FOR OVERCOMING ADAPTIVE RESISTANCE TO ANTI-ANGIOGENIC THERAPY IN OVARIAN CANCER

Abstract Anti-angiogenic therapy such as anti-VEGF antibody (AVA) has been being increasingly applied in patients with ovarian cancer, while vast majority developed adaptive resistance, highlighting the need for new therapies. We have screened a cohort of patients with high-grade serous cancer (HGSC) using cDNA-genomic array and immunohistochemistry. Our results indicated that p130cas [Crk-associated substrate], a central node in FAK/Src-mediated angiogenesis, was significantly upregulated in tumor-associated vascular endothelium, and the clinical analysis showed that HGSC patients with increased vascular p130cas have significantly shorter disease-progression survival than those with lower vascular p130cas levels. Our cell-based studies showed that AVA treatment in endothelial cells led to internalization of a 100-kD fragment of VEGFR2, which was released by caspase-10 cleavage from membrane-tethered VGFR2. This 100-kD form of VEGFR2 bound with TNKS1BP1 (a tankyrase-1-binding protein involved in p53-mediated cell cycle arrest) and internalized into LC3-tagged autophagosomes or translocated into nucleus to initiate cell death. Furthermore, the gene ablation of p130cas with CRISPR/CAS9 in endothelial cells that were originally resistant to AVA therapy re-sensitized them to AVA treatment. Our in vivo studies on targeting vascular p130cas with host-specific siRNA showed a robust inhibition of tumor growth and progression in orthotopic HGSC tumors through initiating autophagy-associated cell death in tumor-associated endothelial cells. To functionally characterize role of vascular p130cas in angiogenesis, we established the p130casflox/flox-Tie2Cre genomic-engineered mice (GEM) model. Using the ID8 syngeneic model, we found that depletion of vascular p130cas diminished resistance to AVA therapy and compromised angiogenesis by inducing elevated VEGFR2/TNKS1BP1 in autophagosomes and nucleus of tumor-associated endothelial cells, which were followed by cell death. To further explore the therapeutic potential of blocking tumor-associated vascular p130cas as a novel anti-angiogenic strategy, we have constituted a cell-permeable, peptide-nanoparticle complex using a p130cas antagonist encapsulated with biodegradable, long-circulating, core-crosslinked polymeric micelles (CCPM). This CCPM-p130cas antagonist contains a mutated Src-binding domain and is linked with Arg-Gly-Asp (RGD) peptide, which specifically targets angiogenic endothelial cells. We also performed the cell-based studies to show that this CCPM-p130cas antagonist is able to bind to the FAK and Src complex with high affinity and effectively block FAK/Src mediated angiogenic property in endothelial cells. Ongoing studies are focused on investigating the therapeutic efficacy and mechanism of actions for RGD-CCPM-p130cas antagonist as a novel anti-angiogenic therapy to overcome adaptive resistance occurred in patients with HGSC. In summary, our studies provided new knowledge regarding the pivotal role of vascular p130cas in tumor-associated endothelial vasculature, and the critical pre-clinical evidences for applying the RGD-CCPM-p130cas antagonist as a novel therapeutic for treatment of ovarian cancer. Citation Format: Yunfei Wen, Alpa M Nick, G Lopez-Berestein, Gary E Gallick, Robert L Coleman Robert , Mien-Chie Hung, and Anil K Sood. A NOVEL TARGET FOR OVERCOMING ADAPTIVE RESISTANCE TO ANTI-ANGIOGENIC THERAPY IN OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr AP21.

Resistance to chemotherapy and anti-angiogenic therapy in ovarian cancer

Ovarian cancer (OC) is the foremost lethal gynaecologic malignancy and among the top five deadliest cancers in women. Current treatment comprises a combination therapy of surgery, platinum-based chemotherapy and anti-vascular endothelial growth factor (VEGF) antibodies. However, patients typically experience a disease relapse within two years. Recurrent OC is incurable and resistance to platins and anti-VEGF treatment is a major determinant of prognosis. Understanding the molecular mechanisms that contribute to tumour metastasis and chemoresistance are essential to improve patient outcome and especially survival. In a current OC model, tumour metastasis and chemoresistance critically depend on the biology of cancer stem cells (CSCs). Recent studies also suggest that intratumour heterogeneity is the main cause of treatment failure due to chemoresistance. Furthermore, the proinflammatory tumour microenvironment seems to contribute to metastasis and chemoresistance. Despite an improved understanding of the complex interplay between classical mechanisms of drug inactivation or efflux, clonal selection and the tumour microenvironment, mechanisms of resistance in human OC are poorly understood. This review summarises current concepts in the treatment of OC, mechanisms of resistance to chemotherapy and angiogenic inhibitors and approaches to overcome drug resistance.

Modern aspects of antiangiogenic therapy in ovarian cancer

The process of angiogenesis is essential for the growth and spread of malignant tumours. Antiangiogenic therapy is deeply embedded in the standard treatment of disseminated ovarian cancer (OC). The numerous studies have demonstrated its efficacy in various stages of the therapy of this disease; bevacizumab is the best-investigated anti-angiogenic drug for OC. This article presents a review and analysis of the most significant studies of the efficacy of anti-angiogenic therapy in ovarian cancer, and describes various aspects of its use in this disease.

The Antiangiogenic Therapy in Ovarian Cancer

The Antiangiogenic Therapy in Ovarian Cancer

Antiangiogenic therapies in ovarian cancer

Antiangiogenic compounds were the first active targeted agents implemented in the treatment of ovarian cancer. Bevacizumab and tyrosine kinase inhibitors such as pazopanib, nintedanib and cediranib target the VEGF pathway, while trebananib was developed as an inhibitor of the angiopoietin pathway. All these compounds have been extensively evaluated and, in this review, we provide a structured overview of the randomized trials that have been performed in both primary and relapsed ovarian cancer. From this data, it is evident that antiangiogenic therapy has its place in ovarian cancer. If not during first-line treatment, then at least at some point for the treatment of relapsed disease. In addition, we address and summarize the trials designed to address the remaining issues related to treatment duration, continuation beyond progression and optimal combination. The future clinical development of angiogenesis inhibitors in ovarian cancer indeed looks at combinations with poly (ADP-ribose) polymerase (PARP) inhibitors, immune checkpoint inhibitors and vascular disrupting agents. Finally, an overview is given of the retrospective translational studies that were performed on the samples of the two pivotal first-line trials GOG(Gynecologic Oncology Group)-218 and ICON(International Collaborative Ovarian Neoplasm study)7, with initial evidence for the predictive value of the BRCA status, some molecular subtypes and histological assessment of microvessel density. If confirmed, these biomarkers could further improve the implementation of antiangiogenic therapy in ovarian cancer.

VEGF Expression to Support Targeted Therapy in Ovarian Surface Epithelial Neoplasms.

Vascular Endothelial Growth Factor (VEGF), a promoter of angiogenesis, is a promising target for anti-angiogenic therapy in ovarian cancer. In our study, we examined the expression of VEGF in the spectrum of epithelial ovarian neoplasms (benign, borderline and malignant) by Immunohistochemistry (IHC). Diagnosing ovarian epithelial neoplasms, examining the expression of VEGF in benign, borderline and malignant neoplasms and correlating it with histological grade and stage of malignant cases. This is a cross-sectional, observational study where, total of 50 cases of surface epithelial ovarian neoplasms were examined for expression of VEGF by IHC. Scoring for VEGF expression was done for each case. A total of 42 of the 50 cases (84%) showed VEGF expression. Out of the 42 positive cases, 19 were high VEGF expressors and 23 were low VEGF expressors. VEGF expression was significantly higher in carcinomas as compared to benign and borderline neoplasms (p=<0.001). All neoplasms of serous morphology were positive for VEGF. High VEGF expression was significantly associated with high grade (p=0.003) and stage (p=0.001) of disease. Ovarian surface epithelial neoplasms significantly express VEGF. Though, some VEGF expression was noted in benign and some borderline neoplasms, high VEGF expression was noted only in carcinomas and one case of borderline serous papillary tumour. Thus, these results suggest that epithelial ovarian tumours are candidates for VEGF targeting therapy as most of them are dependent on VEGF for progression.

CXCR2 Inhibition Combined with Sorafenib Improved Antitumor and Antiangiogenic Response in Preclinical Models of Ovarian Cancer.

Antiangiogenic therapy is important for the treatment of gynecological cancer. However, the therapeutic benefit derived from these treatments is transient, predominantly due to the selective activation of compensatory proangiogenic pathways that lead to rapid development of resistance. We aimed to identify and target potential alternative signaling to anti-vascular endothelial growth factor (VEGF) therapy, with a view toward developing a combination of antiangiogenic agents to provide extended therapeutic benefits. We developed a preclinical in vivo phenotypic resistance model of ovarian cancer resistant to antiangiogenic therapy. We measured dynamic changes in secreted chemokines and angiogenic signaling in tumors and plasma in response to anti-VEGF treatment, as tumors advanced from the initial responsive phase to progressive disease. In tumors that progressed following sorafenib treatment, gene and protein expression levels of proangiogenic CXC chemokines and their receptors were significantly elevated, compared with responsive tumors. The chemokine (C-X-C motif) ligand 8 (CXCL8), also known as interleukin-8 (IL-8) increase was time-dependent and coincided with the dynamics of tumor progression. We used SB225002, a pharmacological inhibitor of chemokine (C-X-C motif) receptor 2 (CXCR2), to disrupt the CXC chemokine-mediated functions of ovarian cancer cells in in vitro assays of cell growth inhibition, spheroid formation, and cell migration. The combination of CXCR2 inhibitor with sorafenib led to a synergistic inhibition of cell growth in vitro, and further stabilized tumor progression following sorafenib in vivo. Our results suggest that CXCR2-mediated chemokines may represent an important compensatory pathway that promotes resistance to antiangiogenic therapy in ovarian cancer. Thus, simultaneous blockage of this proangiogenic cytokine pathway using CXCR2 inhibitors and the VEGF receptor (VEGFR) pathway could improve the outcomes of antiangiogenic therapy.

Abstract 1935: Gene expression analysis reveals distinct pathways of resistance to antiangiogenic therapy in ovarian cancer

Abstract Purpose: The rapid development of resistance after an initial response phase is a major challenge of antiangiogenic therapies. The molecular mechanisms underlying clinical resistance to antiangiogenic therapies are not yet well understood. We aimed to identify potential mediators of resistance to antiangiogenic therapy, with a view toward eventually developing therapeutic approaches to improve antiangiogenic therapies. Methods: We developed preclinical in vivo phenotypic resistance models of antiangiogenic therapy using human ovarian carcinoma cells. We used two representative anti-VEGF agents to block VEGF (bevacizumab, 10 mg/kg BIW, IP) or its receptor (sorafenib, 30 mg/kg daily, PO). The treatment was given until tumors showed a long-term trend toward continued progression after an initial response (resistant tumor). Whereas treatment-sensitive tumors were defined by a long-term trend toward stable disease or regression. We conducted next generation sequencing to compare changes in the gene expression in resistant and sensitive tumors, distinguishing their origin (tumor vs stroma cells). To get a more detailed perspective of the overall changes in gene expression, Gene Set Enrichment Analysis (GSEA) was performed by pair-wise comparison according to treatment outcome (resistant vs sensitive) with respect to bevacizumab and sorafenib, of which the entire MSigDB collections were compared to. Further, significantly enriched pathways were validated with clinical gene expression profiling studies of various tumor types deposited in GEO and ArrayExpress. Results: Our GSEA analysis revealed significant differences (FDR&amp;lt;0.25) in enrichment of various pathways between sensitive and resistant tumors. We observed ERK, P38 MAPK, ATP dependent helicase activity, and phosphatidylinositide 3-kinases pathways are differentially enriched between sensitive and resistant phenotypes of bevacizumab-treated group. In sorafenib-resistant group, six pathways were enriched including E2F1, KRAS and PDGF regulated pathways. Conclusions: Here, we report distinct pathways of response to bevacizumab and sorafenib in preclinical ovarian cancer models, which may provide critical insights into ovarian tumor's adaption during anti-VEGF blockade. These pathways may also provide important clues for identifying synergistic therapeutic strategies to overcome or delay resistance to antiangiogenic agents. Citation Format: Bharat Kumar Devapatla, Pharavee Jaiprasart, Sukyung Woo. Gene expression analysis reveals distinct pathways of resistance to antiangiogenic therapy in ovarian cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1935. doi:10.1158/1538-7445.AM2015-1935

The emerging role of anti-angiogenic therapy in ovarian cancer

The introduction of new therapeutic agents into clinical practice of ovarian cancer, in addition to the role of surgery and chemotherapy, has been the subject of numerous studies because this tumor remains worldwide the most lethal gynecological cancer. It is now known that angiogenesis plays a vital role for ovarian physiology, but also in ovarian carcinogenesis and so it has become the main target of ovarian cancer treatment. In this review, the most common molecular pathways of angiogenesis have been investigated leading to the identification of novel targets, including monoclonal antibodies and tyrosine kinase inhibitors. The fundamental targets of anti-angiogenic drugs are vascular endothelial growth factor receptor and its ligand, but also platelet-derived growth factor, fibroblast growth factor and angiopoietin. Moreover, improved knowledge of angiogenic process allowed the discovery of other molecules, such as semaphorins, neuropilins, clusterin, some transcriptional factors, and the identification of features, including stemness, epithelial-mesenchymal transition, downregulation of certain microRNAs, the alteration of immune system, that contribute to angiogenesis and possibly to resistance mechanisms. The following patent and literature review aim to highlight recent findings of approved and novel anti-angiogenic drugs that make the treatment of patients with ovarian cancer a rapidly growing field of oncology.

Bevacizumab as front-line treatment for newly diagnosed epithelial cancer

Ovarian cancer is the leading cause of death due to gynecological tumors. Despite the progress made during the last two decades in the surgery and chemotherapy of ovarian cancer, more than 70% of patients with advanced ovarian cancer will recur and die. Improvements in this field are coming from a better knowledge of the biology and the development of new-targeted agents. Bevacizumab, is a monoclonal antibody against VEGF that has shown activity as a monotherapy in recurrent ovarian cancer. The addition of bevacizumab to the front-line therapy of ovarian cancer has produced a benefit in progression-free survival in two randomized Phase III trials. This benefit seems to be greater in patients with more advanced disease. However, several questions remain to be clarified in the future, specially the optimal patient selection based on predictive biomarkers and the duration of therapy. Nevertheless, for the first time, the addition of a biologically targeted agent has shown an improvement in progression-free survival in the front-line treatment of advanced ovarian cancer and it is a proof of concept of the potential value of antiangiogenic therapy in ovarian cancer.

Novel Antiangiogenic Therapies in Ovarian Cancer

Epithelial ovarian cancer is the leading cause of death in the developed world for women with gynecologic carcinomas. Despite the effectiveness of platinum salts and taxanes as primary treatments, approximately 80% of women will recur and for them prognosis with available treatments is poor. Of the novel mechanisms under active investigation, there is ample evidence to indicate that angiogenesis is important to the development, progression and poor prognosis of ovarian cancer. Novel treatments are therefore required. A number of agents are undergoing evaluation, including vascular disrupting agents, angiogenesis inhibitors, tyrosine kinase inhibitors and agents targeting the folate receptor. At present, Phase III data are only available for the VEGF-targeted monoclonal antibody, bevacizumab, and that has demonstrated a progression-free survival benefit when used in combination with first-line paclitaxel/carboplatin and continued as maintenance therapy. The strategy of inhibiting angiogenesis in ovarian cancer remains promising. However, other agents in development may point to other important targets in ovarian cancer.

Anti-angiogenic Agents in Ovarian Cancer: Dawn of a New Era?

Epithelial ovarian cancer is a leading cause of cancer-related death for women both in the United States and worldwide, and the effectiveness of cytotoxic chemotherapy has plateaued. Angiogenesis plays an important role in ovarian cancer biology, and exploration of anti-angiogenic agents in this disease has demonstrated anti-tumor activity both as monotherapy and in combination with cytotoxic chemotherapy. However, key questions remain regarding the use of these drugs in ovarian cancer, such as where in treatment should they be used, should these drugs be used as single agents or combined with chemotherapy, can and which biomarkers predict efficacy, are there efficacy and toxicity differences amongst the various agents, what are the cost-benefit ratios of these therapies, and are the patient outcome improvements observed in completed studies significant enough to warrant widespread use of these drugs? Here, we review recent progress and discuss ongoing controversies regarding the use of anti-angiogenic therapies in ovarian cancer.

Antiangiogenic therapies in ovarian cancer

Standard palliative options in the context of platinum-resistant metastatic disease, such as ovarian cancer, include a variety of single-agent chemotherapy drugs all of which afford objective response rates of approximately 10–20% and median overall survival of only approximately 4–8 months. More recently, molecular-targeted approaches have been explored in this disease, with bevacizumab being the most extensively studied and promising candidate. Bevacizumab and other VEGF-targeted agents have demonstrated activity in ovarian cancer, both as a single agent and in combination. Toxicities observed with this class of agent have included hypertension, proteinuria, thromboembolic events, impaired wound healing, neurologic complications and gastrointestinal perforation. However, overall this class of drugs is well tolerated and represents a novel therapeutic choice for clinicians.

Collateral damage: toxic effects of targeted antiangiogenic therapies in ovarian cancer.

First-line chemotherapy fails in more than 20% of patients with epithelial ovarian cancer and about 40-50% of women who respond to initial treatment relapse within 2 years. In the recurrent setting, second-line chemotherapeutic agents have a 15-20% response rate with no cures. Fortunately, clinical investigations that have assessed the efficacy of new, biologically targeted therapies have reinvigorated therapeutic options for patients living with ovarian and other malignancies. In view of the fact that ovarian cancer is one of the most angiogenic neoplasms, there is great hope that implementing targeted agents with antiangiogenic properties will improve outcomes. However, as experience grows with the antitumour activity of these drugs, new toxic effects are emerging. The effects of antiangiogenic agents on molecules and processes that also have physiologically important roles in healthy tissues are at the crux of these toxic effects, or "collateral damage". This review discusses the leading toxic effects encountered and anticipated in clinical investigation and practice with antiangiogenic agents in patients with ovarian cancer, with particular focus on potential management strategies.

Anti-angiogenic therapy in ovarian cancer: a great expectation to be confirmed

Anti-angiogenic therapy in ovarian cancer: a great expectation to be confirmed

Impact of vessel maturation on antiangiogenic therapy in ovarian cancer

The purpose of this study was to examine the functional and therapeutic significance of pericytes in ovarian cancer vasculature. Tumor vessel morphologic condition and efficacy of endothelial and pericyte targeting were examined with the use of in vivo ovarian cancer models. The expression of platelet-derived growth factor (PDGF) ligands and receptors was examined in endothelial, pericyte-like, and ovarian cancer cells. Relative to normal vessels, tumor vasculature was characterized by loosely attached pericytes in reduced density. PDGF-BB was expressed predominantly by the endothelial and cancer cells, whereas PDGFRbeta was present in pericyte-like cells. PDGF-BB significantly increased the migration of and VEGF production by pericyte-like cells; PDGFRbeta blockade abrogated these effects. Dual VEGF (VEGF-Trap) and PDGF-B (PDGF-Trap) targeted therapy was more effective in inhibiting in vivo tumor growth than either agent alone. Aberrations in the tumor microenvironment contribute to endothelial cell survival. Strategies that target both endothelial cells and pericytes should be considered for clinical trials.

Antiangiogenic therapy for ovarian cancer

To highlight the current antiangiogenic compounds being evaluated as single agents or in association with chemotherapy in the treatment of ovarian cancer, as well as the rationale for their development. Several proangiogenic factors may be potential targets for antiangiogenic therapy in ovarian cancer. Bevacizumab, a monoclonal antibody against vascular endothelial growth factor, has been evaluated as a single agent in two phase II clinical trials and in combination with chemotherapy in three phase II studies, with promising results. This agent is also being evaluated in association with chemotherapy in two phase III clinical trials, both in the treatment and in the maintenance settings. Heparanase inhibitors and inhibitors of platelet-derived growth factor signalling remain as potential agents to be investigated in phase II trials. The development of biomarkers to define appropriate dosing regimens and predict which patients may benefit from antiangiogenic therapies is of great importance. Data from preclinical and clinical studies reported in the last 2 years demonstrate the importance of several proangiogenic factors in the prognosis of ovarian cancer, suggesting possible new targets for antiangiogenic therapy. The agents that are currently being investigated in phase II and III clinical trials include bevacizumab, erlotinib, sunitinib, sorafenib and vascular endothelial growth factor Trap, and the results of these trials will have significant implications in the future management of ovarian cancer.