Abstract LB-314: CSF-1R inhibitor JNJ-28312141 reduces antiangiogenic therapy-induced myeloid cell infiltration and mesenchymal shift
Authors: Piao Yuji , Liang Ji , Henry Verlene , Holmes Lindsay , de Groot John F. 
Published: August 2012

Glioblastoma is the most common and malignant primary brain tumor in adults. Despite maximal tumor resection, radiation and chemotherapy, the tumor's high degree of infiltration leads to 100% recurrence and an average life expectancy after diagnosis of about 12 to 14 months. Vascular endothelial growth factor (VEGF) and other pro-angiogenic factors have been identified as critical mediators of angiogenesis in glioblastoma. Inhibition of angiogenesis results in a high radiographic response rate but ultimately all patients’ progress on this therapy. An increase in monocyte/macrophage recruitment has been associated with resistance to antiangiogenic therapy in preclinical mouse xenograft models and in patients. We hypothesized that combining antiangiogenic therapy with therapies inhibiting macrophage infiltration may delay resistance and prolong animal survival. In our glioma stem cell model, we evaluated the impact of bevacizumab alone and in combination with JNJ-28312141 (a novel colony-stimulating factor-1 receptor/FMS-related receptor tyrosine kinase-3 inhibitor) on the recruitment of myeloid cells, microvascular density, and animal survival. Four days after orthotopic implantation of 1× 105 NSC11 glioma stem cells, mice were randomized to treatment with bevacizumab, JNJ-28312141, or the combination of bevacizumab plus JNJ-28312141 and followed for survival (n=8-10 per group). JNJ-28312141 did not prolong survival compared to control. However, JNJ-28312141 combined with bevacizumab significantly reduced tumor vascularity (microvascular density measured using Factor VIII) and prolonged survival compared with bevacizumab alone (p=0.04). We compared the F4/80+ myeloid cell population in xenograft tumors using immunohistochemistry and immunofluorescence. The number of F4/80+ myeloid cells was significantly less in mice treated with JNJ-28312141 and bevacizumab compared with mice treated with bevacizumab alone (p&lt;0.01). To evaluate the impact of treatment on the expression of mesenchymal markers, we quantified YKL-40 protein expression using immunofluorescence. Bevacizumab increased the expression of YKL-40 compared to controls and this increase in expression was significant blocked in the mice treated with the combination of bevacizumab and JNJ -28312141. These results suggest that resistance to antiangiogenic therapy can be partly overcome in glioblastoma by combining anti-VEGF therapy with an inhibitor of macrophages. In our orthotopic glioma model, CSF-1R inhibition is associated with a decrease in the recruitment and infiltration of F4/80+ cells into tumor and a decrease in mesenchymal marker expression. Our studies provide a new strategy to prolong the efficacy of antiangiogenic therapy and accelerate the integration of combination therapies into clinical trials.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-314. doi:1538-7445.AM2012-LB-314