Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by
peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved
therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of
lapatinib and
nilotinib against the mouse
schwannoma SC4 (Nf2 -/-) cell line. We then examined the efficacy of
everolimus,
nilotinib,
lapatinib,
bevacizumab and radiation (RT) as mono- and combination
therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 -/-) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748).
Lapatinib,
nilotinib and RT significantly reduced
tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas
bevacizumab and
everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed
nilotinib or
lapatinib as single agents (
nilotinib vs. nilotinib + RT, p = 0.0001;
lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of
tumors even 14 days
after treatment was stopped. The combination of either
lapatinib or
nilotinib with RT resulted in greater delays in
tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted
therapy may have a role in addressing progressive PNST in patients with NF2.