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GEO help: Mouse over screen elements for information. |
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| Status |
Public on May 20, 2016 |
| Title |
A paracrine IGF1/IGF1R-PI3K signaling loop underlies resistance to CSF-1R inhibition in GBM |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Glioblastoma multiforme (GBM) is the most aggressive form of glioma, and is notorious for its terminal prognosis and lack of responsiveness to current treatment approaches. The brain tumor microenvironment (TME) represents a largely untapped reservoir of therapeutic target options in GBM. Here we have focused on the interplay between glioma cells and tumor-associated macrophages/ microglia (TAMs). TAMs accumulate in the gliomas with disease progression, and depend on colony stimulating factor 1 receptor (CSF-1R) signaling for survival. In a recent study from our laboratory, mice bearing high-grade gliomas were treated with a CSF-1R inhibitor, BLZ945 (Novartis), and tumors regressed significantly after just 7 days of treatment (PMID: 24056773). Here we investigate whether long-term treatment of high-grade gliomas with BLZ945 would result in stable management of disease in a mouse model of proneural GBM. We show that ~44% of mice survived to the trial end point (EP) with minimal disease by MRI and histology, whereas ~56% of mice showed tumor recurrence (Reb). Serial transplantation of rebound tumor cells into naïve animals re-established BLZ945 responsiveness, suggesting a role for the microenvironment in supporting recurrent disease. Indeed, RNA-seq analysis on FACS purified tumor cells and TAMs from EP and Reb tumors showed elevated PI3K signaling in Reb tumors, driven by a heterotypic paracrine interaction between TAM-derived IGF-1 and tumor cell IGF-1R. We performed combination trials to block IGF-1R or downstream PI3K signaling in rebound tumors with BLZ945 treatment, and were able to significantly prolong overall survival. Given that CSF-1R inhibitors are currently in clinical trials for multiple cancer types including for GBM, understanding the molecular mechanisms that underlie non-responsive/ resistant tumors is timely and critical.
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| Overall design |
Tumor cells and tumor -associated macrophages (TAMs) were sorted from Vehicle, Endpoint, and Rebound tumors following BLZ945 treatment.
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| Contributor(s) |
Bowman RL, Quail DF, Joyce JA |
| Citation(s) |
27199435 |
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| Submission date |
May 21, 2015 |
| Last update date |
Mar 19, 2019 |
| Contact name |
Robert L Bowman |
| E-mail(s) |
bowmanr@mskcc.org
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| Phone |
6468882059
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| Organization name |
MSKCC
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| Department |
HOPP
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| Lab |
Levine Lab
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| Street address |
430 East 67th Street
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| City |
New York |
| State/province |
NY |
| ZIP/Postal code |
10065 |
| Country |
USA |
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| Platforms (1) |
| GPL13112 |
Illumina HiSeq 2000 (Mus musculus) |
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| Samples (32)
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| Relations |
| BioProject |
PRJNA284594 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE69104_counts_mat.txt.gz |
950.8 Kb |
(ftp)(http) |
TXT |
| Processed data are available on Series record |
| Raw data not provided for this record |
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