Rationale: Benign peripheral nerve tumors called neurofibromas are a major source of morbidity for patients with neurofibromatosis type 1 (NF1). Some neurofibroma Schwann cells aberrantly express the epidermal growth factor receptor (EGFR). When the human EGFR is expressed in Schwann cells (CNPase-hEGFR mice), a neurofibroma-like phenotype develops (Ling, Wu et al., Cancer Cell, in press). Here we used the CNPase-hEGFR mouse model to test response to the EGFR antagonist Cetuximab (ImClone Systems). Experimental design: We treated wild type and CNPase-EGFR mice twice weekly with Cetuximab or carrier between 0-2 weeks, 1-3 weeks, 2-4 weeks, 3-5 weeks, birth-6 weeks, 6-8 weeks or 6-12 weeks of age. We analyzed nerve histology and tested for nerve sensory alteration by hot-plate testing at 3 months of age. We monitored mast cell chemoattractant levels using quantitative real-time PCR. A second series of experiments monitored EGFR phosphorylation and Schwann cell proliferation after drug exposure between 0 and 2 weeks of age. Results: We found that CNPase-hEGFR mice show hypoalgesia, consistent with disruption of neuron-glial interaction previously described in CNPase-hEGFR mouse nerves. When we administered Cetuximab for only 2 weeks beginning at birth, nerve hypertrophy, mast cell accumulation, collagen deposition and distrupted axon-glial interactions characteristic of this model were all normal at three months of age. Hot plate test results confirmed histology and electron microscopy data. Mast cell chemoattractants BDNF, MCP-1, SCF, VEGF, and TGF-β1, which may account for mast cell accumulation and fibrosis in this model, were each reduced by Cetuximab. Treatment from birth to six weeks did not enhance drug efficacy, and treatment initiated after 2 weeks of age were not effective in reversing nerve phenotypes. In a second set of experiments, we tested for Cetuximab effects on Schwann cells during the critical 2-week window after birth. We found that drug exposure blocked both EGFR phosphorylation and Schwann cell proliferation in mutant mice during the first 2 weeks after birth. Conclustions: Sensory testing as well as histology can be used to monitor therapeutic efficacy in CNPase-hEGFR mice. The results suggest that application of anti-EGFR therapeutics in young animals blocks tumorigenesis by halting a crucial step (perhaps Schwann cell proliferation) in a cascade of events that leads to complex changes characteristic of neurofibroma formation. Supported by NIH R01 NS28840 and DAMD 17-02-1-0679 to N.R. J. W. is a DAMD Neurofibromatosis Fellow.
[Proc Amer Assoc Cancer Res, Volume 46, 2005]