Targeted inhibition of the centromere-associated protein E (CENP-E) with GSK923295A is effective in preclinical models of human neuroblastoma.

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA 2999 Neuroblastoma (NB) is a common solid tumor of childhood that causes significant morbidity and mortality despite intensive chemotherapy. We therefore seek to identify novel therapeutics based on tumor biology. Using mRNA expression profiling, we identified several genes involved in mitotic spindle assembly, including the centromere-associated protein E ( CENP-E ), that were differentially overexpressed in the more aggressive subsets of NBs, including those with MYCN amplification. We evaluated the efficacy of GSK923295A, a selective and potent inhibitor of CENP-E, in preclinical models of NB. In vitro activity of GSK923295A was evaluated in 15 NB cell lines with the ACEA Biosciences RT-CES system that measures electrical impedance of adherent cells for real-time quantification of cell proliferation. IC50 was calculated from the AUC across a 4 log dose range (1-10,000 nM). All NB cell lines showed inhibition of proliferation with a median IC50 of 62 nM (range 27-267 nM). GSK923295A also showed significant single agent activity against the NB-1643 cell line ( MYCN amplified) xenografted into CB17 scid-/- mice. Mice were randomized to GSK923295A 125mg/kg IP or with vehicle (N=10/arm) on days 1, 2 and 3 for two weeks for a total of 6 doses, following xenotransplantation and establishment of a tumor at 200 mm3. There was significant tumor growth delay in the GSK923295A treatment arm versus control ( P < 0.0001). No toxicity was observed since GSK923295A does not inhibit murine Cenp-e. These data demonstrate that CENP-E inhibition is an effective strategy for inhibiting tumor proliferation in preclinical models of NB. Ongoing work in additional cell line models in vitro and in vivo will determine if there are biological surrogates for anti-tumor sensitivity and establish the optimum dosing schedule for early phase clinical trials.