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 dosedependent 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. [Cancer Res 2008;68(5):1520-8]

Neurofibromatosis-1 regulates mTOR-mediated astrocyte growth and glioma formation in a TSC/Rheb-independent manner

“…Immunoreactivity was visualized with the Vectastain avidin-biotin complex and 3,3′-diaminobenzidine (Vector Laboratories). TUNEL labeling was performed as previously described (44). Representative sections were photographed with a digital camera (Optronics) attached to an inverted microscope (Nikon).…”

The long and winding road to rational treatment of cancer associated with LKB1/AMPK/TSC/mTORC1 signaling

“…Preclinical evaluation of the suppressive and preventive efficacy of rapamycin for PJS using Lkb1 þ /À mice has revealed that rapamycin effectively reduced the tumor burden in these animals (Wei et al, 2008(Wei et al, , 2009Robinson et al, 2009;. Also in mouse models for NF1 and PHTS, treatment with rapamycin has been shown to reduce tumor growth (Podsypanina et al, 2001;Hegedus et al, 2008;Squarize et al, 2008). At present, one open-label phase II clinical trial is recruiting PJS patients for suppressive therapy with everolimus to determine if this drug can diminish gastrointestinal polyps (clinicaltrials.…”

The ecology of brain tumors: lessons learned from neurofibromatosis-1

“…In astrocytes, neurofibromin loss leads to mTOR-dependent increases in cell proliferation, which reflect mTOR regulation of Rac1 (Sandsmark et al, 2007) and STAT3 (Banerjee et al, 2010). These differences have profound implications with respect to therapeutic drug design and support the use of rapamycin, an immunosuppressant drug, to specifically inhibit the mTOR pathway in Nf1-deficient gliomas (Hegedus et al, 2008) and Schwann cell malignancies (Johansson et al, 2008), and MEK inhibitors for other NF1-associated tumor types.…”