cMET Blockade Augments Response to Radiation Without Damaging Hearing in Models of Schwannoma

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Vestibular schwannomas, the hallmark of neurofibromatosis type 2 (NF2), are typically treated with both surgery and radiation therapy. Unfortunately, both treatments can cause debilitating hearing loss. An adjunct therapy is needed that would enhance the efficacy and reduce the dosage of radiation.

In a recent study, patients with NF2-associated vestibular schwannomas were treated with bevacizumab, a monoclonal antibody that inhibits vascular endothelial growth factor (VEGF). Improvements in hearing were inversely associated with the baseline plasma level of hepatocyte growth factor (HGF), which suggests that signaling by HGF and its proto-oncogene receptor cMET, may play a role in hearing loss.

Both HGF expression and cMET activation have been shown to be deregulated in a number of major human cancers and to correlate with a poor prognosis. Moreover, increasing evidence implicates cMET as a major mechanism of resistance to chemotherapy, radiation therapy and targeted therapies.

Now, Scott R. Plotkin, MD, director of the Massachusetts General Hospital Neurofibromatosis Clinic, and colleagues have determined that cMET blockade is effective against both mouse and human schwannomas. More strikingly, they found that HGF/cMET blockade can enhance radiation efficacy and help lower the radiation dose. Their report appears in Proceedings of the National Academy of Sciences.

The research team developed a schwannoma mouse model that is true to clinical findings in patients with vestibular schwannoma, in that tumor size and growth rate do not correlate with hearing loss. Using that model, they observed that crizotinib, a cMET inhibitor that is FDA-approved for non-small cell lung cancer, enhanced schwannoma radiosensitivity by enhancing DNA damage.

Furthermore, combining crizotinib with low-dose radiation was as effective as high-dose radiation.

Crizotinib had no adverse effect on hearing in the animals, but it failed to alleviate tumor-induced hearing loss. The researchers explain that cMET blockade presumably did not change tumor HGF levels. A cMET gene knockdown study confirmed the role of the cMET pathway in mediating the effects of crizotinib.

The researchers then evaluated the potential of cMET blockade in human vestibular schwannomas. They compared 17 NF2-associated schwannomas and 10 sporadic schwannomas with four normal great auricular nerves. In both types of schwannomas, median relative cMET mRNA levels were significantly higher than in normal nerves.

Validation of the RNA data at the protein level showed that HGF expression and cMET activation correlated with tumor growth and cyst formation.

For further exploration, the researchers grew human NF2-associated vestibular schwannomas and meningiomas in brain slices obtained from immunodeficient nude mice. Crizotinib treatment significantly decreased cMET phosphorylation and tumor cell proliferation, and it increased tumor cell apoptosis.

The authors conclude that combined treatment with cMET inhibitors may enhance radiosensitivity and circumvent the onset of resistance to radiation therapy in patients with vestibular schwannoma. An alternate strategy might be to combine blockade of VEGF and cMET with radiation.

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