The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma.
Iddo PaldorSara AbbadiNicolas BonneXiaobu YeFausto J RodriguezDavid RowshanshadMariaLisa ItzoeVeronica VigilarMarco GiovanniniHenry BremJaishri O BlakeleyBetty M TylerPublished in: Journal of neuro-oncology (2017)
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.
Keyphrases
- signaling pathway
- chronic myeloid leukemia
- positive breast cancer
- lps induced
- pi k akt
- induced apoptosis
- metastatic breast cancer
- oxidative stress
- nuclear factor
- dna repair
- low dose
- inflammatory response
- peripheral nerve
- cell cycle arrest
- multiple sclerosis
- epithelial mesenchymal transition
- dna damage
- locally advanced
- endothelial cells
- big data
- high dose
- machine learning
- squamous cell carcinoma
- cell proliferation
- rectal cancer
- high throughput