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|Ref Type||Journal Article|
|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.)|
|Date||2016 May 20|
|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.|
|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|