SU11248 inhibits tumor growth and CSF-1R-dependent osteolysis in an experimental breast cancer bone metastasis model.
The aim of the study was to investigate inhibitory effects of the receptor tyrosine kinase (RTK) inhibitor SU11248 against CSF-1R and osteoclast (OC) formation. We developed an in vivo model of breast cancer metastasis to evaluate efficacy of SU11248 against tumor growth and tumor-induced osteolysis in bone. The in vitro effects of SU11248 on CSF-1R phosphorylation, OC formation and function were evaluated. Effects on 435/HAL-Luc tumor growth in bone were monitored by in vivo bioluminescence imaging (BLI), and inhibition of osteolysis was evaluated by measurement of serum pyridinoline (PYD) concentration and histology. Phosphorylation of the receptor for M-CSF (CSF-1R) expressed by NIH3T3 cells was inhibited by SU11248 with an IC50 of 50-100 nM, consistent with CSF-1R belonging to the class III split kinase domain RTK family. The early M-CSF-dependent phase of in vitro murine OC development and function were inhibited by SU11248 at 10-100 nM. In vivo inhibition of osteolysis was confirmed by significant lowering of serum PYD levels following SU11248 treatment of tumor-bearing mice (P = 0.047). Using BLI, SU11248 treatment at 40 mg/kg/day for 21 days showed 64% inhibition of tumor growth in bone (P = 0.006), and at 80 mg/kg/day showed 89% inhibition (P = 0.001). Collectively, these data suggest that SU11248 may be an effective and tolerated therapy to inhibit growth of breast cancer bone metastases, with the additional advantage of inhibiting tumor-associated osteolysis.
Murray
Lesley J
LJ
SUGEN, Inc. South San Francisco, California, USA. drlesleymurray@yahoo.com
Abrams
Tinya J
TJ
Long
Kelly R
KR
Ngai
Theresa J
TJ
Olson
Lisa M
LM
Hong
Weiru
W
Keast
Paul K
PK
Brassard
Jacqueline A
JA
O'Farrell
Anne Marie
AM
Cherrington
Julie M
JM
Pryer
Nancy K
NK
D000818:Animals; D001859:Bone Neoplasms / Q000473:pathology* / Q000503:physiopathology* / Q000556:secondary; D001943:Breast Neoplasms / Q000473:pathology; D002448:Cell Adhesion; D007211:Indoles / Q000494:pharmacology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010010:Osteoclasts; D010014:Osteolysis; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology*; D020794:Receptor Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D000077210:Sunitinib; D014407:Tumor Cells, Cultured
D007211:Indoles; D011758:Pyrroles; D020794:Receptor Protein-Tyrosine Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D000077210:Sunitinib