Journal
ONCOTARGET
Volume 8, Issue 57, Pages 96496-96505Publisher
IMPACT JOURNALS LLC
DOI: 10.19632/oncotarget.20410
Keywords
adaptive resistance; anti-VEGF therapy; tumor associated macrophages; tumor microenvironment; CSF1R inhibition
Categories
Funding
- Cancer Prevention Research Institute of Texas [RP101502, RP101489]
- Foundation for Women's Cancer grant
- Deutsche Forschungsgemeinschaft (DFG)
- American Cancer Society Research Professor Award
- NIH training grant [T32CA009666, T32-CA101642-11]
- Blanton-Davis Ovarian Cancer Research Program
- Foundation for Women's Cancer
- RGK Foundation
- Shared Instrumentation Award from the Cancer Prevention Research Institution of Texas [RP121010]
- Ovarian Cancer Research Fund, Inc. (Program Project Development Grant)
- Ovarian Cancer Research Fund, Inc.
- National Institutes of Health through M. D. Anderson's Cancer Center Support Grant [CA016672]
- Cancer Prevention and Research Institute of Texas [RP110595, RP120214]
- Frank McGraw Memorial Chair in Cancer Research
- Liz Tilberis Early Career Award
- National Institutes of Health [CA016672, U01CA213759, CA177909, CA109298, UH3TR000943, P50 CA083639, P50 CA098258, R00CA190783]
- Judi A. Rees ovarian cancer research fund
- Keck Center of the Gulf Coast Consortia, on the Training Program in Biomedical Informatics, National Library of Medicine (NLM) [T15LM007093]
- Collen's Dream Foundation
- Texas Center for Cancer Nanomedicine
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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.
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