Abstract #259: The selective CSF-1R inhibitor AZ683 reduces tumor associated macrophages and inhibits growth of breast cancer xenograft models

CSF-1 regulates the survival, proliferation, differentiation and function of mononuclear phagocytes, in addition to the spreading and motility of macrophages. As a major component of the stromal infiltrate, tumor associated macrophages (TAMs) have been linked to poor prognosis in multiple tumor types including breast cancer and promote angiogenesis, invasion and metastasis. As the CSF-1 receptor, CSF-1R therefore appears to be an attractive target for anti cancer therapy. We have discovered a novel potent and selective ATP competitive inhibitor of CSF-1R tyrosine kinase activity, AZ683. The Ki value of this compound for CSF-1R is 8nM and it demonstrates >250 fold selectivity for CSF-1R over 95 other kinases evaluated in vitro. AZ683 also inhibits CSF-1R in cells as demonstrated by its ability to block CSF-1 stimulated CSF-1R signaling and growth in 3T3 cells engineered to express human CSF-1R and CSF-1 dependent mouse macrophage cell lines. Growth inhibition is associated with a dose and time-dependent induction of G1 arrest and subsequent cell death, consistent with the phenotype associated with CSF-1 withdrawal. In contrast, AZ683 has little or no effect on growth of FGF-stimulated 3T3 cells and 58 human cancer cell lines, including the breast cancer cell lines MDA-MB-231 and MCF-7. Inhibition of CSF1R in vivo is demonstrated by the ability of AZ683 to reduce pCSF1R levels in a 3T3 allograft expressing constitutively activated CSF1R, reduce circulating monocytes and reduce F/480 positive TAMs in various xenograft models. Dose dependent reduction in TAMs in MDA-MB-231 and MCF7 breast cancer xenografts is associated with inhibition of tumor growth. In MCF7 xenografts, this is linked to a reduction in microvessel density as assessed by CD31 staining. In summary, AZ683 is a selective CSF1R inhibitor that targets has the ability to deplete TAMs and supports evaluation of this approach for anticancer therapy. Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 259.