Targeting the c-Met pathway potentiates glioblastoma responses to γ-radiation

Research output: Contribution to journalArticle

Abstract

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 down-stream 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/ribozyrtie 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, longterm 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.

Original languageEnglish (US)
Pages (from-to)4479-4486
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number12
DOIs
StatePublished - Jun 15 2005

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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