Macrophage depletion through colony stimulating factor 1 receptor pathway blockade overcomes adaptive resistance to anti-VEGF therapy.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • 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

Published Date

  • November 14, 2017

Published In

Volume / Issue

  • 8 / 57

Start / End Page

  • 96496 - 96505

PubMed ID

  • 29228548

Pubmed Central ID

  • PMC5722500

Electronic International Standard Serial Number (EISSN)

  • 1949-2553

Digital Object Identifier (DOI)

  • 10.18632/oncotarget.20410


  • eng

Conference Location

  • United States