Anti-tumor efficacy of selective FMS inhibitors in mouse models of cancer
Authors: Brian West, Gideon Bollag, Jiazhong Zhang, Betsy Burton, Adhirai Marimuthu, Gaston Habets, Kam Zhang, Yoshi Suzuki, Ivana Cheung, Kevin Eng, Hongyao Zhu, Marika Nespi, Angela Oh, Rafe Shellooe, Hoa Nguyen, Bernice Wong, Catherine Luu, Ben Powell, Chao Zhang, James Tsai, Prabha Ibrahim, Keith Nolop, K Hirth, D Artis, Ryan Bremer
Journal: Cancer Research (2008)

5384  Tumor-associated macrophages have been correlated with poor outcome in several types of cancer, although a cause-effect relation has not been established. The cytokine CSF-1 regulates the growth, differentiation, and activation of macrophages, and there is evidence in mouse models to support the hope that interference with CSF-1 signaling may lead to a benefit for cancer patients. CSF-1 is also a key regulator of osteoclast differentiation, so this benefit conceivably may extend to delay or prevent the effects of pain and bone resorption commonly observed in cancer patients reaching a metastatic stage involving bone.  We have developed a series of small molecule compounds that inhibit the protein tyrosine kinase activity of FMS, the transmembrane receptor for CSF-1. Chemistry designs were iteratively guided by co-crystallography with the FMS catalytic domain, and a portfolio was obtained of compounds with high-affinity ( 100-fold).  Biochemical activities were confirmed using cell-based assays, including an assay in which Ba/F3 pre-B cells were engineered to express a fusion protein having the N-terminus of BCR linked to the intracellular catalytic domain of FMS. Whereas the parent Ba/F3 cells require IL-3 for growth, these Ba/F3-FMS cells do not, and addition of the FMS inhibitors to the Ba/F3-FMS cultures caused apoptosis and death in the absence, but not presence, of added IL-3.  When Ba/F3-FMS cells (5x106 cells) were introduced through the tail vein into female athymic nude mice, a splenomegaly was observed, with spleen weights increasing 20-fold from 0.06 g to 1.2 g after 14-17 days. Oral administration of the FMS inhibitors to the injected mice reduced the splenomegaly in a dose-dependent manner, indicating that the compounds have pharmacokinetic properties acceptable for reaching effective doses in animals. Dosing during only the first 3 days or the last 3 days reduced the splenomegaly partially, indicating that the growth of Ba/F3-FMS cells in the spleen is sensitive throughout the growth period to inhibition of the FMS kinase, suggesting this model is a useful mimic of longer-term inhibitor treatment regimens.  The FMS inhibitors were also tested in an MCF-7 breast cancer xenograft model. MCF-7 cells were passed as tumor fragments from tumors established in nude mice, and no estradiol supplementation was given. After 4 weeks of treatment, the FMS inhibitor reduced the tumor volume by 40%. In an MDA-MB-231-LUC breast cancer metastasis model, in which cells were injected into the left heart ventricle, treatment with FMS inhibitor from days 28 to 34 after injection led to a 60% decrease in tumor burden in the bone. These initial studies are supportive of further tests of FMS as a target in breast cancer, and work on these compounds and newer derivatives are in progress.