Preclinical cancer therapy in a mouse model of neurofibromatosis-1 optic glioma.

Abstract

Mouse models of human cancers afford unique opportunities to evaluate novel therapies in preclinical trials. For this purpose, we analyzed three genetically engineered mouse (GEM) models of low-grade glioma resulting from either inactivation of the neurofibromatosis-1 (Nf1) tumor suppressor gene or constitutive activation of KRas in glial cells. Based on tumor proliferation, location, and penetrance, we selected one of these Nf1 GEM models for preclinical drug evaluation. After detection of an optic glioma by manganese-enhanced magnetic resonance imaging, we randomized mice to either treatment or control groups. We first validated the Nf1 optic glioma model using conventional single-agent chemotherapy (temozolomide) currently used for children with low-grade glioma and showed that treatment resulted in decreased proliferation and increased apoptosis of tumor cells in vivo as well as reduced tumor volume. Because neurofibromin negatively regulates mammalian target of rapamycin (mTOR) signaling, we showed that pharmacologic mTOR inhibition in vivo led to decreased tumor cell proliferation in a dose-dependent fashion associated with a decrease in tumor volume. Interestingly, no additive effect of combined rapamycin and temozolomide treatment was observed. Lastly, to determine the effect of these therapies on the normal brain, we showed that treatments that affect tumor cell proliferation or apoptosis did not have a significant effect on the proliferation of progenitor cells within brain germinal zones. Collectively, these findings suggest that this Nf1 optic glioma model may be a potential preclinical benchmark for identifying novel therapies that have a high likelihood of success in human clinical trials.

• Authors: Balazs Hegedus, Debasish Banerjee, Tu-Hsueh Yeh, Stefan Rothermich, Arie Perry, Joshua B Rubin, Joel R Garbow, David H Gutmann
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 5 Pg. 1520-8 (Mar 01 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18316617 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• Antineoplastic Agents, Alkylating
• Neurofibromin 1
• Dacarbazine
• Protein Kinases
• MTOR protein, human
• mTOR protein, mouse
• TOR Serine-Threonine Kinases
• Sirolimus
• Temozolomide

Topics

• Animals
• Antineoplastic Agents, Alkylating (pharmacology)
• Apoptosis
• Cell Proliferation
• Dacarbazine (analogs & derivatives, pharmacology)
• Disease Models, Animal
• Eye Neoplasms (genetics, pathology, therapy)
• Magnetic Resonance Imaging
• Mice
• Mice, Transgenic
• Neurofibromin 1 (genetics, physiology)
• Optic Nerve Glioma (genetics, pathology, therapy)
• Protein Kinases (metabolism)
• Signal Transduction
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases
• Temozolomide