Abstract A33: Combinatorial targeting of tumor-associated macrophages/ microglia and radiotherapy in gliomas

Eighty percent of tumors that develop in the central nervous system are malignant gliomas, with over half being glioblastoma multiforme (GBM), the most aggressive form of this disease. Unfortunately, there have been minimal improvements in the survival of patients with GBM and these tumors remain essentially incurable. Even following treatment with standard of care therapy (surgery, radiation and temozolomide), the overall 5-year survival rate of patients diagnosed with GBM is less than 5%, highlighting the urgent need for novel and alternative therapeutic strategies to treat GBM. In GBM patients and mouse models of the disease, the major non-cancerous cell type in the glioma microenvironment is tumor-associated macrophages/microglia (TAMMs). TAMMs can account for as much as 30% of the tumor mass in human GBM, and their accumulation is associated with poor patient prognosis. We previously used an inhibitor of colony stimulating factor 1 receptor (CSF-1R), BLZ945, to target macrophages in the RCAS-PDGF-B; nestin-TVA, Ink4a/Arf null mouse model of gliomagenesis, which faithfully recapitulates the hallmarks of human GBM. We found that CSF-1R inhibition dramatically improves survival in a long-term intervention trial and markedly regresses established high-grade lesions. To determine the translational clinical potential for CSF-1R inhibition, we designed preclinical trials in combination with radiation, which is part of the standard treatment for GBM patients. We treated established GBMs with fractionated radiation concomitant with acute, short-term BLZ945 treatment and observed that the overall survival of animals was significantly extended compared to single treatment modalities. Moreover, incorporating long-term treatment with BLZ945 in tumors treated with fractionated radiation lead to a dramatic reduction in tumor recurrence, suggesting that reversing cancer-induced M2 macrophage programming has the potential to render gliomas more prone to response to radiotherapy. Interestingly, treatment of IR-resistant gliomas with BLZ945 de novo resulted in efficient regression of the disease, which may have important translational implications. We are currently examining the molecular mechanisms by which re-educating TAMMs increases radiation sensitivity. Together these results demonstrate critical roles for CSF1R-dependent TAMMs in promoting glioma malignancy, and highlight the clinical potential for CSF-1R inhibitors. Citation Format: Leila Akkari, Daniela F. Quail, Marsha L. Quick, Jason T. Huse, James C. Sutton, Johanna A. Joyce. Combinatorial targeting of tumor-associated macrophages/ microglia and radiotherapy in gliomas. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr A33.