Publication Date:
2016-05-21
Description:
Macrophages accumulate with glioblastoma multiforme (GBM) progression and can be targeted via inhibition of colony-stimulating factor-1 receptor (CSF-1R) to regress high-grade tumors in animal models of this cancer. However, whether and how resistance emerges in response to sustained CSF-1R blockade is unknown. We show that although overall survival is significantly prolonged, tumors recur in 〉50% of mice. Gliomas reestablish sensitivity to CSF-1R inhibition upon transplantation, indicating that resistance is tumor microenvironment-driven. Phosphatidylinositol 3-kinase (PI3K) pathway activity was elevated in recurrent GBM, driven by macrophage-derived insulin-like growth factor-1 (IGF-1) and tumor cell IGF-1 receptor (IGF-1R). Combining IGF-1R or PI3K blockade with CSF-1R inhibition in recurrent tumors significantly prolonged overall survival. Our findings thus reveal a potential therapeutic approach for treating resistance to CSF-1R inhibitors.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Quail, Daniela F -- Bowman, Robert L -- Akkari, Leila -- Quick, Marsha L -- Schuhmacher, Alberto J -- Huse, Jason T -- Holland, Eric C -- Sutton, James C -- Joyce, Johanna A -- F31CA167863/CA/NCI NIH HHS/ -- P30 CA008748/CA/NCI NIH HHS/ -- R01CA148967/CA/NCI NIH HHS/ -- Canadian Institutes of Health Research/Canada -- New York, N.Y. -- Science. 2016 May 20;352(6288):aad3018. doi: 10.1126/science.aad3018.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. ; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Department of Oncology, University of Lausanne, CH-1066, Lausanne, Switzerland. Ludwig Institute for Cancer Research, University of Lausanne, CH-1066, Lausanne, Switzerland. ; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. ; Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, WA 98109, USA. ; Novartis Institutes for Biomedical Research, Emeryville, CA 94608, USA. ; Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY 10065, USA. Department of Oncology, University of Lausanne, CH-1066, Lausanne, Switzerland. Ludwig Institute for Cancer Research, University of Lausanne, CH-1066, Lausanne, Switzerland. johanna@joycelab.org.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/27199435" target="_blank"〉PubMed〈/a〉
Print ISSN:
0036-8075
Electronic ISSN:
1095-9203
Topics:
Biology
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Chemistry and Pharmacology
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Computer Science
,
Medicine
,
Natural Sciences in General
,
Physics
