Ispinesib (SB-715992) a kinesin spindle protein (KSP) inhibitor has single agent activity and enhances the efficacy of standard-of-care therapies in pre-clinical models of breast cancer.

Abstract

Abstract Abstract #2122 Background: Ispinesib is a novel highly specific small molecule inhibitor of kinesin spindle protein (KSP), a motor protein that is essential for formation of a bipolar mitotic spindle and for cell cycle progression through mitosis. KSP is expressed only in proliferating cells and not in post-mitotic neurons. In preclinical models and clinical studies thus far, ispinesib exhibits a favorable safety profile compared with tubulin-targeted therapies. Ispinesib has demonstrated clinical activity in patients with locally advanced or metastatic breast cancer that failed to respond/relapsed after treatment with taxanes and anthracyclines, and is currently being evaluated in a Phase I/II trial as first-line treatment in chemotherapy-naïve patients with locally advanced (Stage IIIB) or metastatic (Stage IV) breast cancer. In the current study, we explored the anti-tumor activity of ispinesib as a single agent and in combination with approved therapies in preclinical models of breast cancer. Methods: We implanted cells representative of hormone receptor positive luminal tumors (MCF-7), tumors overexpressing Her-2 (KPL4, HCC1954, BT474) or triple-negative basal tumors (MDA-MB-468) in immunodeficient female Nude or SCID mice. We started dosing Ispinesib when tumor volume reached 100-150mm3 and monitored xenograft growth for 60 days post treatment. Results: Ispinesib administered i.p. as a single agent on a q4dx3 schedule at its MTD induced tumor regressions in all five models of human breast cancer. In particular, all treated MDA-MB-468 xenografts (7/7) were tumor free survivors at 90 days post dosing. In tumors collected at different times post-dosing, we observed a strong mitotic arrest, inhibition of proliferation, and increased apoptosis by western blotting and IHC analyses of PH3, Ki67 and cleaved PARP respectively. We also determined the efficacy of ispinesib in combination with standard-of-care therapies in breast cancer. In the Her2 overexpressing models, the combination of ispinesib and herceptin markedly improved response rate and efficacy over either single agent. Tumor Growth Inhibition (TGI) was 99% for the combined agents, 67% for herceptin and 78% for ispinesib in KPL4. A similar benefit was found by combining ispinesib with lapatinib in BT474. Finally, ispinesib enhanced the anti-tumor activity of doxorubicin, causing an increase in TGI in 2 separate models (in MCF7, TGI was 86% for the combined agents, 39% for doxorubicin and 67% for ispinesib). Additional combination studies with capecitabine are under investigation.Conclusions: In distinct models of human breast cancer, ispinesib exhibited significant anti-tumor activity as a single agent. When used in combination, ispinesib enhanced the activity of standard-of-care therapies herceptin, lapatinib and doxorubicin. These data suggest that ispinesib may offer clinical benefit in the treatment of breast cancer, and support clinical studies of ispinesib in combination with these therapies. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2122.