Abstract
Abstract Prostate tumors that have metastasized to bone frequently proliferate in bone and induce significant bone pain and pathological remodeling, all of which are difficult to control fully using currently available therapies. Colony stimulating factor-1 (CSF-1) regulates the survival, proliferation, differentiation and function of cells in the monocyte lineage including macrophages and osteoclasts. Human studies have reported a greater expression of CSF-1 and its receptor, CSF-1R (also known as c-Fms), in tumor and stromal cells of metastatic prostate cancers versus non-metastatic prostate cancers. To assess the role of CSF-1R in pain and disease progression in bone from prostate cancer, a novel small molecule inhibitor of CSF-1R, PLX3397, was administered to mice that were injected in the femur marrow space with ACE-1 canine prostate cancer cells. Intrafemoral injection of prostate cancer cells resulted in significant growth of tumor, which in turn induced significant skeletal pain and massive formation of pathological, disordered, woven bone. Sustained administration of PLX3397 started on day 12 after the tumors were well established and pathological bone remodeling was evident. Six weeks treatment with PLX3397 significantly attenuated (∼50%) prostate tumor cell growth (p=0.018), bone cancer pain behaviors (p<0.001) and the prostate cancer cell induced pathological remodeling of the bone (p<0.001). These results suggest that blockade of CSF-1R/CSF-1 signaling by PLX3397 is highly effective in not only reducing prostate cancer growth in the bone, but also prostate cancer induced bone pain and pathological remodeling. PLX3397 is currently undergoing Phase 2 clinical testing in patients with a variety of tumors, and these data further support its evaluation in patients with prostate cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A246.
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