Targeting the c-Met Pathway Potentiates Glioblastoma Responses to γ-Radiation

• Published in: Clinical cancer research 2005-06, Vol.11 (12), p.4479-4486
• Main Authors: LAL, Bachchu, SHULI XIA, ABOUNADER, Roger, LATERRA, John
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; apoptosis; Apoptosis - genetics; Apoptosis - radiation effects; Biological and medical sciences; Blotting, Northern; brain tumor; Cell Line, Tumor; Gamma Rays; Gene Expression Regulation, Neoplastic; Genetic Vectors - genetics; Glioblastoma - genetics; Glioblastoma - pathology; Glioblastoma - radiotherapy; hepatocyte growth factor; Hepatocyte Growth Factor - genetics; Hepatocyte Growth Factor - metabolism; Humans; Immunoblotting; Immunohistochemistry; In Situ Nick-End Labeling; Ki-67 Antigen - analysis; Medical sciences; Mice; Mice, Nude; Neurology; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; RNA, Catalytic - genetics; RNA, Catalytic - metabolism; scatter factor; Tumors of the nervous system. Phacomatoses; Xenograft Model Antitumor Assays - methods
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-05-0166

Purpose: Resistance to current cytotoxic therapies limits the treatment of most solid malignancies. This results, in part, from the overactivation of receptor tyrosine kinases and their downstream pathways in tumor cells and their associated vasculature. In this report, we ask if targeting the multifunctional mitogenic, cytoprotective, and angiogenic scatter factor/hepatocyte growth factor (SF/HGF)/c-Met pathway potentiates antitumor responses to γ-radiation. Experimental Design: Endogenous expression of SF/HGF and c-Met was targeted in U87 MG human malignant glioma cells and xenografts using chimeric U1/ribozymes. The effects of U1/ribozymes ± γ-radiation on glioma cell proliferation, apoptosis, xenograft growth, and animal survival were examined. Results: U1/ribozymes knocked down SF/HGF and c-Met mRNA and protein levels, sensitized cells to γ-radiation ( P < 0.005), and enhanced radiation-induced caspase-dependent cytotoxicity in vitro ( P < 0.005). Intravenous U1/ribozyme therapy as liposome/DNA complexes or radiation alone modestly and transiently inhibited the growth of s.c. U87 xenografts. Combining the therapies caused tumor regression and a 40% tumor cure rate. In animals bearing intracranial xenografts, long-term survival was 0% in response to radiation, 20% in response to intratumoral adenoviral-based U1/ribozyme delivery, and 80% ( P < 0.0005) in response to combining U1/ribozymes with radiation. This apparent synergistic antitumor response was associated with a ∼70% decrease in cell proliferation ( P < 0.001) and a ∼14- to 40-fold increase in apoptosis ( P < 0.0001) within xenografts. Conclusions: Targeting the SF/HGF/c-Met pathway markedly potentiates the antiglioma response to γ-radiation. Clinical trials using novel SF/HGF/c-Met pathway inhibitors in glioma and other malignancies associated with c-Met activation should ultimate include concurrent radiation and potentially other cytotoxic therapeutics.