Abstract
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.
Highlights
Ovarian cancer is the leading cause of death from gynecological cancers in the U.S When treated with current standard-of-care chemotherapy, the five-year survival rate of advanced disease remains low
Based on the above findings of the upregulation of CXCR2 expression and multiple ELR+CXC proangiogenic cytokines that mediate their angiogenic effects via CXCR2 receptor, we investigated CXCR2-mediated cytokine effects using SB225002, a small molecule inhibitor of chemokine receptor CXCR2 (IL-8R), in combination with sorafenib in vitro
To date, encouraging results have been obtained with ovarian cancer trials incorporating VEGF-pathway inhibitors, the therapeutic antibody bevacizumab, and small molecule receptor tyrosine kinase inhibitors (TKIs)[27]
Summary
Ovarian cancer is the leading cause of death from gynecological cancers in the U.S When treated with current standard-of-care chemotherapy, the five-year survival rate of advanced disease remains low. A number of antiangiogenic agents, including the therapeutic antibody against VEGF bevacizumab and multi-targeted kinase inhibitors of VEGF receptors (VEGFR), have been actively investigated or are in development as treatments for advanced disease. Treatment with bevacizumab provided a progression free survival (PFS) benefit in advanced ovarian cancer when administered in combination with chemotherapy [7, 8]. Several VEGFR-targeting multi-kinase inhibitors such as nintedanib, trebananib, pazopanib, sunitinib, sorafenib, cediranib have been tested in various phases of ovarian cancer clinical trials [9] Some of these agents, including pazopanib, nintedanib, cediranib, and trebananib, have been evaluated in randomized Phase III clinical trials, and all have demonstrated a progression-free survival (PFS) benefit [10]. Understanding the mechanisms of tumor escape from anti-VEGF therapy is critical to finding strategies to circumvent resistance. Combining different antiangiogenic therapies may be a strategy to provide lasting therapeutic benefits
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