Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy
© Lyons et al. Anti-angiogenesis therapy has shown clinical benefit in patients with highgrade 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 proangiogenic 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 antiangiogenesis 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.
Lyons, YA; Pradeep, S; Wu, SY; Haemmerle, M; Hansen, JM; Wagner, MJ; Villar-Prados, A; Nagaraja, AS; Dood, RL; Previs, RA; Hu, W; Zhao, Y; Mak, DH; Xiao, Z; Melendez, BD; Lizee, GA; Mercado-Uribe, I; Baggerly, KA; Hwu, P; Liu, J; Overwijk, WW; Coleman, RL; Sood, AK
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