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

Autor:	Lyons YA; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Pradeep S; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Wu SY; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Haemmerle M; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Hansen JM; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Wagner MJ; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Villar-Prados A; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Nagaraja AS; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Dood RL; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Previs RA; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Hu W; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Zhao Y; Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Mak DH; Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Xiao Z; Department of Melanoma Medical Oncology-Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Melendez BD; Department of Melanoma Medical Oncology-Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Lizee GA; Department of Melanoma Medical Oncology-Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Mercado-Uribe I; Department of Pathology, Division of Pathology and Laboratory Medicine, Section of Gynecologic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Baggerly KA; Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Hwu P; Department of Melanoma Medical Oncology-Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Liu J; Department of Pathology, Division of Pathology and Laboratory Medicine, Section of Gynecologic Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Overwijk WW; Department of Melanoma Medical Oncology-Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Coleman RL; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA., Sood AK; Departments of Gynecologic Oncology and Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Center for RNAi and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.; Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Jazyk:	angličtina
Zdroj:	Oncotarget [Oncotarget] 2017 Aug 24; Vol. 8 (57), pp. 96496-96505. Date of Electronic Publication: 2017 Aug 24 (Print Publication: 2017).
DOI:	10.18632/oncotarget.20410
Abstrakt:	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. Competing Interests: CONFLICTS OF INTEREST RLC serves on the advisory board and as a consultant for Genentech/Roche.
Databáze:	MEDLINE
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