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Targeting the c-Met pathway potentiates glioblastoma responses to gamma-radiation
Bachchu Lal1, Shuli Xia, Roger Abounader
1Department of Neurology, The Johns Hopkins University School of Medicine and The Kennedy Krieger Research Institute, Baltimore, Maryland 21205, USA.
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 gamma-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 +/- gamma-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 gamma-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 approximately 70% decrease in cell proliferation (P < 0.001) and a approximately 14- to 40-fold increase in apoptosis (P < 0.0001) within xenografts.
Conclusions:
Targeting the SF/HGF/c-Met pathway markedly potentiates the anti-glioma response to gamma-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.
Insights
Targeting the scatter factor/hepatocyte growth factor (SF/HGF)/c-Met pathway enhances gamma-radiation therapy for solid tumors. Combining SF/HGF/c-Met inhibition with radiation significantly boosts antitumor responses and improves survival rates in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Solid tumor resistance to chemotherapy is a major clinical challenge.
- Overactivation of receptor tyrosine kinases (RTKs) and downstream pathways drives tumor growth and angiogenesis.
- The scatter factor/hepatocyte growth factor (SF/HGF)/c-Met pathway is implicated in tumor cell proliferation, survival, and angiogenesis.
Purpose of the Study:
- To investigate whether targeting the SF/HGF/c-Met pathway can enhance antitumor responses to gamma-radiation.
- To evaluate the efficacy of combined SF/HGF/c-Met inhibition and gamma-radiation in preclinical models of malignant glioma.
Main Methods:
- U87 MG human malignant glioma cells and xenografts were treated with chimeric U1/ribozymes to target SF/HGF and c-Met expression.
- The effects of U1/ribozymes alone or in combination with gamma-radiation were assessed on glioma cell proliferation, apoptosis, xenograft growth, and animal survival.
Main Results:
- U1/ribozymes effectively reduced SF/HGF and c-Met levels, sensitizing glioma cells to gamma-radiation and enhancing radiation-induced apoptosis in vitro.
- Combined U1/ribozyme therapy and gamma-radiation led to significant tumor regression and a 40% cure rate in subcutaneous xenografts.
- In intracranial xenografts, the combination therapy resulted in an 80% long-term survival rate, a substantial increase compared to radiation or U1/ribozyme therapy alone.
Conclusions:
- Targeting the SF/HGF/c-Met pathway significantly potentiates the anti-glioma effects of gamma-radiation.
- The observed synergistic antitumor response is linked to reduced tumor cell proliferation and increased apoptosis.
- Concurrent use of SF/HGF/c-Met pathway inhibitors with radiation therapy warrants clinical investigation for glioma and other malignancies with c-Met activation.
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