Activity of the kinesin spindle protein inhibitor ispinesib (SB-715992) in models of breast cancer.
OBJECTIVE
Ispinesib (SB-715992) is a potent inhibitor of kinesin spindle protein, a kinesin motor protein essential for the formation of a bipolar mitotic spindle and cell cycle progression through mitosis. Clinical studies of ispinesib have shown a 9% response rate in patients with locally advanced or metastatic breast cancer and a favorable safety profile without significant neurotoxicities, gastrointestinal toxicities, or hair loss. To better understand the potential of ispinesib in the treatment of breast cancer, we explored the activity of ispinesib alone and in combination with several therapies approved for the treatment of breast cancer.


METHODS
We measured the ispinesib sensitivity and pharmacodynamic response of breast cancer cell lines representative of various subtypes in vitro and as xenografts in vivo and tested the ability of ispinesib to enhance the antitumor activity of approved therapies.


RESULTS
In vitro, ispinesib displayed broad antiproliferative activity against a panel of 53 breast cell lines. In vivo, ispinesib produced regressions in each of five breast cancer models and tumor-free survivors in three of these models. The effects of ispinesib treatment on pharmacodynamic markers of mitosis and apoptosis were examined in vitro and in vivo, revealing a greater increase in both mitotic and apoptotic markers in the MDA-MB-468 model than in the less sensitive BT-474 model. In vivo, ispinesib enhanced the antitumor activity of trastuzumab, lapatinib, doxorubicin, and capecitabine and exhibited activity comparable with paclitaxel and ixabepilone.


CONCLUSIONS
These findings support further clinical exploration of kinesin spindle protein inhibitors for the treatment of breast cancer.
Purcell
James W
JW
Cytokinetics, Inc., South San Francisco, California 94080, USA.
Davis
Jefferson
J
Reddy
Mamatha
M
Martin
Shamra
S
Samayoa
Kimberly
K
Vo
Hung
H
Thomsen
Karen
K
Bean
Peter
P
Kuo
Wen Lin
WL
Ziyad
Safiyyah
S
Billig
Jessica
J
Feiler
Heidi S
HS
Gray
Joe W
JW
Wood
Kenneth W
KW
Cases
Sylvaine
S
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy*; D002277:Carcinoma / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D016547:Kinesins / Q000037:antagonists & inhibitors*; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D001549:Benzamides; C470243:KIF11 protein, human; D011799:Quinazolines; C508757:ispinesib; D016547:Kinesins