Preclincial testing of Sorafenib and RAD001 in the Nfflox/flox;DhhCre mouse model of plexiform neurofibroma using magnetic resonance imaging
J Wu, E Dombi, E Jousma, R Scott Dunn… - Pediatric blood & …, 2012 - Wiley Online Library
J Wu, E Dombi, E Jousma, R Scott Dunn, D Lindquist, BM Schnell, MO Kim, AR Kim…
Pediatric blood & cancer, 2012•Wiley Online LibraryAbstract 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 …
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 …
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 Nf1flox/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.
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