Broad antitumor activity in breast cancer xenografts by motesanib, a highly selective, oral inhibitor of vascular endothelial growth factor, platelet-derived growth factor, and Kit receptors.
OBJECTIVE
Angiogenesis plays a critical role in breast cancer development and progression. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor that regulates endothelial cell proliferation and survival. We investigated the effects of motesanib, a novel, oral inhibitor of VEGF receptors 1, 2, and 3; platelet-derived growth factor receptor; and Kit receptor, on the growth of xenografts representing various human breast cancer subtypes.


METHODS
Athymic nude mice were implanted with MCF-7 (luminal) or MDA-MB-231 (mesenchymal) tumor fragments or Cal-51 (mixed/progenitor) tumor cells. Once tumors were established, animals were randomized to receive increasing doses of motesanib alone or motesanib plus cytotoxic chemotherapy (docetaxel, doxorubicin, or tamoxifen).


RESULTS
Across all three xenograft models, motesanib treatment resulted in significant dose-dependent reductions in tumor growth, compared with vehicle-treated controls, and in marked reductions in viable tumor fraction and blood vessel density. No significant effect on body weight was observed with compound treatment compared with control-treated animals. Motesanib did not affect the proliferation of tumor cells in vitro. There was a significantly greater reduction in xenograft tumor growth when motesanib was combined with docetaxel (MDA-MB-231 tumors) or with the estrogen receptor modulator tamoxifen (MCF-7 tumors), compared with either treatment alone, but not when combined with doxorubicin (Cal-51 tumors).


CONCLUSIONS
Treatment with motesanib alone or in combination with chemotherapy inhibits tumor growth in vivo in various models of human breast cancer. These data suggest that motesanib may have broad utility in the treatment of human breast cancer.
Coxon
Angela
A
Department of Oncology Research, Amgen, Inc., Thousand Oaks, California, USA.
Bush
Tammy
T
Saffran
Douglas
D
Kaufman
Stephen
S
Belmontes
Brian
B
Rex
Karen
K
Hughes
Paul
P
Caenepeel
Sean
S
Rottman
James B
JB
Tasker
Andrew
A
Patel
Vinod
V
Kendall
Richard
R
Radinsky
Robert
R
Polverino
Anthony
A
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D001835:Body Weight / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008325:Mammary Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D009841:Oligonucleotides; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors*; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism*; D011897:Random Allocation; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
D020533:Angiogenesis Inhibitors; D007211:Indoles; D009841:Oligonucleotides; D010982:Platelet-Derived Growth Factor; D042461:Vascular Endothelial Growth Factor A; D009536:Niacinamide; D019009:Proto-Oncogene Proteins c-kit; C519562:imetelstat