Therapeutic targeting of human hepatocyte growth factor with a single neutralizing monoclonal antibody reduces lung tumorigenesis.
The hepatocyte growth factor (HGF)/c-Met signaling pathway is involved in lung tumor growth and progression, and agents that target this pathway have clinical potential for lung cancer treatment. L2G7, a single potent anti-human HGF neutralizing monoclonal antibody, showed profound inhibition of human HGF-induced phosphorylated mitogen-activated protein kinase induction, wound healing, and invasion in lung tumor cells in vitro. Transgenic mice that overexpress human HGF in the airways were used to study the therapeutic efficacy of L2G7 for lung cancer prevention. Mice were treated with the tobacco carcinogen, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, over 4 weeks. Beginning at week 3, i.p. treatment with 100 mug L2G7 or isotype-matched antibody control, 5G8, was initiated and continued through week 15. The mean number of tumors per mouse in the L2G7-treated group was significantly lower than in the control group (1.58 versus 3.19; P = 0.0005). Proliferative index was decreased by 48% (P = 0.013) in tumors from L2G7-treated mice versus 5G8-treated mice, whereas extent of apoptosis was increased in these same tumors by 5-fold (P = 0.0013). Phosphorylated mitogen-activated protein kinase expression was also significantly decreased by 84% in tumors from L2G7-treated mice versus 5G8-treated mice (P = 0.0003). Tumors that arose in HGF transgenic animals despite L2G7 treatment were more likely to contain mutant K-ras, suggesting that targeting the HGF/c-Met pathway may not be as effective if downstream signaling is activated by a K-ras mutation. These preclinical results show that blocking the HGF/c-Met interaction with a single monoclonal antibody delivered systemically can have profound inhibitory effects on development of lung tumors.
Stabile
Laura P
LP
Department of Pharmacology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Rothstein
Mary E
ME
Keohavong
Phouthone
P
Jin
Jide
J
Yin
Jinling
J
Land
Stephanie R
SR
Dacic
Sanja
S
Luong
The Minh
TM
Kim
K Jin
KJ
Dulak
Austin M
AM
Siegfried
Jill M
JM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009361:Neoplasm Invasiveness; D009500:Neutralization Tests; D011230:Precancerous Conditions / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; C066855:HGF protein, human; D017228:Hepatocyte Growth Factor; D020928:Mitogen-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)