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Ref Type Journal Article
PMID (27199435)
Authors Quail DF, Bowman RL, Akkari L, Quick ML, Schuhmacher AJ, Huse JT, Holland EC, Sutton JC, Joyce JA
Title The tumor microenvironment underlies acquired resistance to CSF-1R inhibition in gliomas.
Journal Science (New York, N.Y.)
Vol 352
Issue 6288
Date 2016 May 20
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
TP53 loss glioblastoma sensitive BLZ945 Preclinical Actionable In a preclinical study, treatment with BLZ945 demonstrated some efficacy, specifically a 56% tumor reduction, in transgenic mouse models of glioblastoma with a loss of TP53 (PMID: 27199435). 27199435
PTEN loss glioblastoma no benefit BLZ945 Preclinical Actionable In a preclinical study, BLZ945 resulted in limited benefit in transgenic mouse models of glioblastoma harboring a loss of PTEN (PMID: 27199435). 27199435