Abstract 3850: Efficacy of the selective CSF-1R kinase inhibitor PLX3397 in mouse models of tumor growth and bone metastasis

Macrophages of the tumor microenvironment can facilitate cancer progression and are a possible target for therapy. We have developed PLX3397, an orally-active, selective small molecule inhibitor of the colony stimulating factor-1 receptor (CSF-1R) kinase. CSF-1R is known to control a key signaling pathway for the recruitment of macrophages to tumors, and also for differentiation of osteoclasts mediating the destructive processes of bone metastasis. We show efficacy of PLX3397 in three different animal cancer models. PLX3397, which is currently in Phase I clinical trial, also inhibits the related kinase Kit, although we believe the efficacy observed here primarily reflects CSF-1R inhibition. SK-N-SH human neuroblastoma cells grown as xenografts in female nude mice were inhibited 60% in their growth compared to controls after 18 days oral dosing of PLX3397. This contrasts with a very weak effect on growth of SK-N-SH cells in culture, with an IC50 of 10 μM. A similar lack of growth inhibitory effects of PLX3397 was obtained using several cancer cells and when tested in cell toxicity assays. In a separate study, PLX3397 had little or no effect on the growth of MDA-MB-231 human tumor cells grown as xenografts. These results suggest that the observed inhibition of SK-N-SH cells grown in vivo are mediated by targeting cells of the microenvironment, and further, that this neuroblastoma may be more dependant on the microenvironment than other tumor cells. The MMTV-PyMT transgenic mouse breast cancer model has been used previously to identify mechanisms through which tumor-associated macrophages can enhance metastasis. Using this model, PLX3397 caused a 90% reduction in circulating tumor cells (CTCs), quantified by FACS analysis with a pan-cytokeratin antibody. This decrease was observable after two oral doses given at 18 and 4 hours before a terminal blood sample was taken. A similar decrease in CTCs was observed using QPCR in syngeneic mice orthotopically implanted with a tumor cell line derived from the transgenic mice. PLX3397 also worked at low concentrations in vitro to reduce by 55% the ability of macrophages (purified from tumors) to induce invasive acini in breast cancer cells grown in culture as spheroids. MDA-MB-468 human breast tumor cells injected into the tibia of female SCID mice caused trabecular bone loss as measured by micro-CT, and this bone lysis was associated with a 4-fold elevation in osteoclast number. Oral dosing of PLX3397 prevented both the rise in osteoclasts and the loss of bone, suggesting this compound is able to inhibit the intended CSF-1R target in vivo, and predicting it may offer benefit to cancer patients suffering with bone metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3850.