Abstract 660: Inhibition of centrosomal clustering suppresses tumor growth in vivo

Abstract

Abstract Tumor cells frequently contain multiple centrosomes, associated with the formation of multipolar mitotic spindles and chromosome segregation defects. To allow for bipolar mitotic division, supernumerary centrosomes are clustered into two functional spindle poles (centrosomal clustering). We recently described a phenotype-based small molecule screening strategy directed to induce tumor cells with supernumerary centrosomes to undergo multipolar mitoses, thereby resulting in apoptotic cell death (Rebacz et al., Cancer Res 2007; 67: 6342-6350). We here describe the novel small molecule GF-15, a derivative of griseofulvin and a potent inhibitor of centrosomal clustering, thereby inducing multipolar spindles followed by apoptosis. We tested more than 25 cancer cell lines from hematologic malignancies (including acute and chronic leukemias, lymphomas), solid tumors (including glioblastoma, colon, cervix, and pancreatic cancers) and a wide array of myeloma cell lines. We found mean inhibitory concentrations (IC50) for proliferation and survival in the range of 1-5μM GF-15, associated with activation of caspases 8, 9, and 3. As expected, tumor cell lines displaying only limited centrosomal aberrations or microsatellite instability were less sensitive to treatment with GF-15. Importantly, non-malignant cells without supernumerary centrosomes including PBMCs, immortalized hepatocytes, and bone marrow stromal cells, did not reach their IC50 even at 30μM GF-15. Specifically, cell cycle analysis of synchronized myeloma cells showed marked G2/M arrest, followed by a dramatic increase of the sub-G1 fraction, after treatment with GF-15. In addition, treatment with GF-15 was associated with inhibition of VEGF- and IGF1-triggered myeloma cell migration. Pharmakodynamic studies in vivo revealed rapid renal clearance of GF-15 and metabolites within 6 hours p.i. No acute or chronic toxicity was observed. Finally, both intraperitoneal and oral GF-15 treatment of murine xenograft models of human multiple myeloma resulted in tumor growth inhibition and significantly prolonged survival associated with significant increase of aberrant mitoses in vivo. Taken together, our results demonstrate the in vitro and in vivo anti-tumor efficacy of the first in class small molecule inhibitor of centrosomal clustering with specificity for tumor cells, and strongly support its clinical evaluation to improve patient outcome in both hematologic malignancies and solid tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 660. doi:10.1158/1538-7445.AM2011-660