A  paracrine IGF1/IGF1R-PI3K signaling loop underlies resistance to CSF-1R inhibition in GBM

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.