Abstract
Anti-angiogenesis therapy has shown clinical benefit in patients with high-grade serous ovarian cancer (HGSC), but adaptive resistance rapidly emerges. Thus, approaches to overcome such resistance are needed. We developed the setting of adaptive resistance to anti-VEGF therapy, and performed a series of in vivo experiments in both immune competent and nude mouse models. Given the pro-angiogenic properties of tumor-associated macrophages (TAMs) and the dominant role of CSF1R in macrophage function, we added CSF1R inhibitors following emergence of adaptive resistance to anti-VEGF antibody. Mice treated with a CSF1R inhibitor (AC708) after anti-VEGF antibody resistance had little to no measurable tumor burden upon completion of the experiment while those that did not receive a CSF1R inhibitor still had abundant tumor. To mimic clinically used regimens, mice were also treated with anti-VEGF antibody and paclitaxel until resistance emerged, and then a CSF1R inhibitor was added. The addition of a CSF1R inhibitor restored response to anti-angiogenesis therapy, resulting in 83% lower tumor burden compared to treatment with anti-VEGF antibody and paclitaxel alone. Collectively, our data demonstrate that the addition of a CSF1R inhibitor to anti-VEGF therapy and taxane chemotherapy results in robust anti-tumor effects.
Highlights
Angiogenesis and VEGF are known to play an important role in the progression of ovarian and other cancers, making bevacizumab an important drug in standard treatment regimens [1]
The key findings from our study are a decrease in tumor burden, ascites, and macrophage content when a CSF1R inhibitor is combined with anti-VEGF therapy in the setting of adaptive resistance
We show a change in expression of p-AKT, FAK, and PD-L1 markers in macrophages from tumor treated with CSF1R inhibition in the setting of adaptive resistance, as compared to samples that continued with only anti-VEGF therapy
Summary
Angiogenesis and VEGF are known to play an important role in the progression of ovarian and other cancers, making bevacizumab an important drug in standard treatment regimens [1]. Even though bevacizumab provides modest increases in survival, patients eventually develop progressive disease and relapse despite continuous anti-VEGF therapy [2]. Of the proposed mechanisms of anti-angiogenic therapy resistance, here we focus on the role of macrophages [3]. Therapy that overcomes adaptive resistance to anti-VEGF therapy by targeting macrophages could potentially improve clinical outcomes of cancer patients. CSF1R inhibition is best described in clinical trials for diffuse-type tenosynovial giant cell tumor (dt-GCT), a disease characterized by overexpression of CSF1 [5]. 78% of patients with evaluable tumor samples showed a significant reduction in CD68+/CD163+ and CSF1R+ macrophages [5] Administration of emactuzumab, a human monoclonal IgG1 antibody against CSF1R, led to objective response in 86% of patients [5]. 78% of patients with evaluable tumor samples showed a significant reduction in CD68+/CD163+ and CSF1R+ macrophages [5]
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