Abstract 3629: BLZ945, a selective c-fms (CSF-1R) kinase inhibitor for the suppression of tumor-induced osteolytic lesions in bone
Authors: Wiesmann Marion , Daniel Dylan L. , Pryer Nancy , Sutton James , Sung Victoria , Wang Tao , Jeffry Ursula , Oei Yoko , Kaufman Susan , Lenahan William , Lee Isabelle , Huh Kay , Sim Janet 
Published: February 2011

Aberrant activation of osteoclasts due to bone metastasis causes osteolysis, skeletal-related events and severe pain in cancer patients. Macrophage-Colony-stimulating Factor (M-CSF) signaling through its receptor c-fms / Colony-Stimulating Factor-1 Receptor (CSF-1R) in the monocytic lineage is essential for osteoclastogenesis, providing an opportunity to inhibit this pathway and suppress tumor-induced osteolysis. BLZ945 is an orally active, potent and selective CSF-1R inhibitor. BLZ945 inhibits CSF-1R activity with an IC50 of 1nM and is more than 1000-fold selective against its closest receptor tyrosine kinase homologs c-KIT and Platelet-derived Growth Factor Receptor beta (PDGFRb) as well as more than 200 additional kinases, confirming the selectivity of the compound. BLZ945 potently inhibited proliferation of the M-CSF-dependent murine leukemia cell line MNFS60 (EC50 67 nM) consistent with the inhibition of the CSF-1R kinase activity. Tyrosine phosphorylation in HEK293 cells overexpressing human CSF-1R was inhibited with an EC50 of 58 nM. Functional activity of BLZ945 was shown by inhibition of osteoclastogenesis using human osteoclast precursors.

The MNFS60 allograft model was used to evaluate the pharmacodynamics of BLZ945 by monitoring dose and time dependent changes in tyrosine phoshorylation of CSF-1R to select doses and regimens for in vivo efficacy studies. A single dose of BLZ945 at 200 mg/kg maximally suppressed CSF-1R phosphorylation of &gt;50% for more than 16 hours in this model and was selected for further evaluation in mouse models of breast (MDA-MB-231Luc) and prostate (PC-3MLuc) tumor-induced osteolysis (TIO). In these models human tumor cells are injected directly into the tibia of nude mice and bone destruction is measured by x-ray analysis and serum levels of tartrate-resistant acid phosphatase 5b (TRAP5b), a marker of osteoclast activity. Daily dosing of BLZ945 at 200 mg/kg resulted in a significant reduction in the progression of osteolysis, with &gt; 50% reduction in osteolytic lesion severity in both TIO models, as compared to vehicle-treated animals. Reductions in serum TRAP5b were also observed at the end of the studies. BLZ945 showed enhanced activity in combination with zoledronate in the PC-3MLuc model, with the combination reducing osteolytic severity scores by 90%. In addition anti-osteolytic activity was observed in a nude rat model of osteolysis induced by intratibial injection of MDA-MB-231 cells. In naïve cynomolgus monkeys, treatment with BLZ945 resulted in dose-dependent reductions of serum TRAP5b and cross-linked collagen (CTX) in both serum and urine, consistent with the expected effect of inhibiting bone resorption. These data support the testing of CSF-1R inhibitors in advanced cancer patients with bone metastases and skeletal related events.

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 3629.