Oncotarget

Priority Research Papers:

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

Yasmin A. Lyons, Sunila Pradeep, Sherry Y. Wu, Monika Haemmerle, Jean M. Hansen, Michael J. Wagner, Alejandro Villar-Prados, Archana S. Nagaraja, Robert L. Dood, Rebecca A. Previs, Wei Hu, Yang Zhao, Duncan H. Mak, Zhilan Xiao, Brenda D. Melendez, Gregory A. Lizee, Imelda Mercado-Uribe, Keith A. Baggerly, Patrick Hwu, Jinsong Liu, Willem W. Overwijk, Robert L. Coleman and Anil K. Sood _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2017; 8:96496-96505. https://doi.org/10.18632/oncotarget.20410

Metrics: PDF 807 views  |   HTML 1342 views  |   ?  


Abstract

Yasmin A. Lyons1, Sunila Pradeep1, Sherry Y. Wu1, Monika Haemmerle1, Jean M. Hansen1, Michael J. Wagner1, Alejandro Villar-Prados1, Archana S. Nagaraja1, Robert L. Dood1, Rebecca A. Previs1, Wei Hu1, Yang Zhao4, Duncan H. Mak,7 Zhilan Xiao5, Brenda D. Melendez5, Gregory A. Lizee5, Imelda Mercado-Uribe6, Keith A. Baggerly4, Patrick Hwu5, Jinsong Liu6, Willem W. Overwijk5, Robert L. Coleman1 and Anil K. Sood1,2,3

1 Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

2 Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

3 Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

4 Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

5 Department of Melanoma Medical Oncology-Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

6 Department of Pathology, Division of Pathology and Laboratory Medicine, Section of Gynecologic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

7 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

Correspondence to:

Anil K. Sood, email:

Keywords: adaptive resistance, anti-VEGF therapy, tumor associated macrophages, tumor microenvironment, CSF1R inhibition

Received: April 18, 2017 Accepted: July 20, 2017 Published: August 24, 2017

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 20410