An orally active small molecule TGF-beta receptor I antagonist inhibits the growth of metastatic murine breast cancer.
BACKGROUND
Transforming growth factor beta (TGF-beta) plays a complex role in breast carcinogenesis. Initially functioning as a tumor suppressor, this cytokine later contributes to the progression of malignant cells by enhancing their invasive and metastatic potential as well as suppressing antitumor immunity. The purpose of this study was to investigate the efficacy of SM16, a novel small molecule ALK5 kinase inhibitor, to treat a highly metastatic, TGF-beta-producing murine mammary carcinoma (4T1).


METHODS
Mice bearing established 4T1 tumors were treated with SM16 intraperitoneally (i.p.) or orally, and primary and metastatic tumor growth was assessed.


RESULTS
SM16 inhibited Smad2 phosphorylation in cultured 4T1 tumor cells as well as primary and metastatic 4T1 tumor tissue. Blockade of TGF-beta signal transduction in 4T1 tumor cells by SM16 prevented TGF-beta-induced morphological changes and inhibited TGF-beta-induced invasion in vitro. When delivered via daily i.p. injection or orally through mouse chow, SM16 inhibited the growth of primary and metastatic 4T1 tumors. Splenocytes isolated from mice on the SM16 diet displayed enhanced IFN-gamma production and antitumor CTL activity. Furthermore, SM16 failed to inhibit the growth and metastasis of established 4T1 tumors in immunodeficient SCID mice.


CONCLUSIONS
Taken together, the data indicate that the antitumor efficacy of SM16 is dependent on an immune-mediated mechanism and that SM16 may represent a safe and effective treatment for metastatic breast cancer.
Rausch
Matthew P
MP
Department of Immunobiology, University of Arizona, Tucson, AZ 85724, USA.
Hahn
Tobias
T
Ramanathapuram
Lalitha
L
Bradley-Dunlop
Deborah
D
Mahadevan
Daruka
D
Mercado-Pimentel
Melania E
ME
Runyan
Raymond B
RB
Besselsen
David G
DG
Zhang
Xiamei
X
Cheung
H-Kam
HK
Lee
Wen-Cherng
WC
Ling
Leona E
LE
Akporiaye
Emmanuel T
ET
D000284:Administration, Oral; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053961:Azabicyclo Compounds / Q000008:administration & dosage*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005455:Fluorescent Antibody Technique; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008819:Mice, Nude; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D053961:Azabicyclo Compounds; D047428:Protein Kinase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; C528106:SM16 compound; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625842:Tgfbr1 protein, mouse