Premium
Preclincial testing of Sorafenib and RAD001 in the Nf flox/flox ;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging
Author(s) -
Wu Jianqiang,
Dombi Eva,
Jousma Edwin,
Scott Dunn R.,
Lindquist Diana,
Schnell Beverly M.,
Kim MiOk,
Kim AeRang,
Widemann Brigitte C.,
Cripe Timothy P.,
Ratner Nancy
Publication year - 2012
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.23015
Subject(s) - sorafenib , neurofibroma , medicine , neurofibromatosis , magnetic resonance imaging , cancer research , plexiform neurofibroma , drug , nuclear medicine , pathology , pharmacology , radiology , hepatocellular carcinoma
Background Neurofibromatosis type 1 (NF1) is an inherited disease predisposing affected patients to variable numbers of benign neurofibromas. To date there are no effective chemotherapeutic drugs available for this slow growing tumor. Molecularly targeted agents that aim to slow neurofibroma growth are being tested in clinical trials. So preclinical models for testing potential therapies are urgently needed to prioritize drugs for clinical trials of neurofibromas. Procedure We used magnetic resonance imaging (MRI) to monitor neurofibroma development in the Nf1 flox/flox ;DhhCre mouse model of GEM grade I neurofibroma. Based on studies implicating mTOR and Raf signaling in NF1 mutant cells, we tested the therapeutic effect of RAD001 and Sorafenib in this model. Mice were scanned to establish growth rate followed by 8 weeks of drug treatment, then re‐imaged after the last dose of drug treatment. Tumor volumes were determined by volumetric measurement. Results We found that rate of tumor growth varied among mice, as it does in human patients. RAD001 inhibited its predicted target pS6K, yet there was no significant decrease in the tumor volume in RAD001 treated mice compared to the vehicle control group. Sorafenib inhibited cyclinD1 expression and cell proliferation in tumors, and volumetric measurements identified significant decreases in tumor volume in some mice. Conclusion The data demonstrate that volumetric MRI analysis can be used to monitor the therapeutic effect in the preclinical neurofibroma drug screening, and suggest that Sorafenib might have clinical activity in some neurofibromas. Pediatr Blood Cancer 2012; 58: 173–180. © 2011 Wiley Periodicals, Inc.