Anti-vascular therapies in ovarian cancer: moving beyond anti-VEGF approaches

Abstract

Resistance to chemotherapy is among the most important issues in the management of ovarian cancer. Unlike cancer cells, which are heterogeneous as a result of remarkable genetic instability, stromal cells are considered relatively homogeneous. Thus, targeting the tumor microenvironment is an attractive approach for cancer therapy. Arguably, anti-vascular endothelial growth factor (anti-VEGF) therapies hold great promise, but their efficacy has been modest, likely owing to redundant and complementary angiogenic pathways. Components of platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), and other pathways may compensate for VEGF blockade and allow angiogenesis to occur despite anti-VEGF treatment. In addition, hypoxia induced by antiangiogenesis therapy modifies signaling pathways in tumor and stromal cells, which induces resistance to therapy. Because of tumor cell heterogeneity and angiogenic pathway redundancy, combining cytotoxic and targeted therapies or combining therapies targeting different pathways can potentially overcome resistance. Although targeted therapy is showing promise, much more work is needed to maximize its impact, including the discovery of new targets and identification of individuals most likely to benefit from such therapies.

Sodium/proton exchanger isoform 1 regulates intracellular pH and cell proliferation in human ovarian cancer

“…CNA alterations may modulate the SLC9A1 expression by endothelin-1 and epidermal growth factor, complementing reports involving endothelin-1 and endothelin receptor A in this type of cancer [40] and endothelin-1 in combination with -arrestin-1 activation increasing chemoresistance [41]. Equally, activation of epidermal growth factor/epidermal growth factor receptor signalling is involved in higher angiogenesis [42] and resistance to paclitaxel [43] showing that inhibition of NHE1 activity results in a higher sensitivity to paclitaxel in breath cancer [47]. Thus, strategies to control NHE1 expression and activity in patients with ovary cancer could be of benefit reducing the adverse patient's outcome of this disease.…”

Cancer-associated fibroblasts regulate endothelial adhesion protein LPP to promote ovarian cancer chemoresistance

“…Two weeks after tumor cell injection, ovarian cancer-bearing mice were the vessel system for improved drug delivery (38)(39)(40)(41). However, several clinical trials in cancer patients have demonstrated that agents targeting VEGF family members convey a progression-free survival advantage but rarely an overall survival advantage, possibly because other potent proangiogenic factors and their downstream effector molecules are present in the tumor microenvironment and endothelial cells, respectively, leading to insufficient suppression of tumor angiogenesis (1,2,42).…”

“…Tumor vasculature plays an important role in the pathogenesis and progression of HGSC and is crucial in modulating the delivery of therapeutic agents (1). Various tumor cell-derived cytokines, including VEGFs and FGFs, are involved in HGSC pathogenesis and progression.…”

“…Although phase I and II trials of the VEGF-α-targeting monoclonal antibody bevacizumab in patients with ovarian cancer yielded encouraging results, phase III trials of the drug as a frontline treatment for ovarian cancer patients (Gynecologic Oncology Group 218 [GOG 218] and International Collaboration on Ovarian Neoplasms 7 [ICON7]) and recurrent ovarian cancer (Ovarian Cancer Study Comparing Efficacy and Safety of Chemotherapy and Anti-Angiogenic Therapy in PlatinumSensitive Recurrent Disease [OCEANS] and Avastin Use in Platinum-Resistant Epithelial Ovarian Cancer [AURELIA]) have demonstrated that bevacizumab yields only a modest improvement in progression-free survival and no significant improvement in overall survival (2)(3)(4)(5). These findings suggest that other proangiogenic mediators and pathways compensate for VEGF blockade and allow angiogenesis to occur, despite anti-VEGF therapy (1). Further research, including that aimed at identifying new proangiogenic targets and markers to optimize patient selection, is essential to maximize the potential of antiangiogenic therapy for ovarian cancer.…”

FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

“…These therapies are approved for treatment of a variety of human cancers (3) and include the monoclonal anti-VEGF antibody bevacizumab (4,5) and multitargeted receptor tyrosine kinase inhibitors (6). However, in most clinical trials, these agents have only offered modest improvements in progression-free survival, without affecting overall survival (7).…”