Magnetic Resonance Imaging Determination of Tumor Grade and Early Response to Temozolomide in a Genetically Engineered Mouse Model of Glioma

Abstract

Purpose: The median survival for patients diagnosed with glioblastoma multiforme, the most common type of brain tumor, is less than 1 year. Animal glioma models that are more predictive of therapeutic response in human patients than traditional models and that are genetically and histologically accurate are an unmet need. The nestin tv-a (Ntv-a) genetically engineered mouse spontaneously develops glioma when infected with ALV-A expressing platelet-derived growth factor, resulting in autocrine platelet-derived growth factor signaling. Experimental Design: In the Ntv-a genetically engineered mouse model, T2-weighted and T1-weighted, contrast-enhanced magnetic resonance images were correlated with histology, glioma grade (high or low), and survival. Magnetic resonance imaging (MRI) was therefore used to enroll mice with high-grade gliomas into a second study that tested efficacy of the current standard of care for glioma, temozolomide (100 mg/kg qdx5 i.p., n = 13). Results:The Ntv-a model generated a heterogeneous group of gliomas, some with high-grade growth rate and histologic characteristics and others with characteristics of lower-grade gliomas. We showed that MRI could be used to predict tumor grade and survival. Temozolomide treatment of high-grade tv-a gliomas provided a 14-day growth delay compared with vehicle controls. Diffusion MRI measurement of the apparent diffusion coefficient showed an early decrease in cellularity with temozolomide, similar to that observed in humans. Conclusions: The use of MRI in the Ntv-a model allows determination of glioma grade and survival prediction, distribution of mice with specific tumor types into preclinical trials, and efficacy determination both by tumor growth and early apparent diffusion coefficient response.Gliomas are the most common form of brain tumor, with more than half belonging to the most aggressive subtype (i.e., glioblastoma multiforme) at initial diagnosis. Although aggressive combination therapies, including surgery, radiation, and chemotherapy, are commonly used, median survival for patients diagnosed with glioblastoma multiforme is less than 1 year (1). Part of the reason for the deficit in significant progress has been the lack of predictive preclinical models. Development and validation of models that accurately recapitulate the complex-activated signaling pathways involved in glial transformation and tumor progression has been hindered due to lack of available methods for selecting and placing tumored mice on study and for efficient end point determination. However, recent developments in preclinical imaging technologies are facilitating the development of genetically engineered mouse (GEM) models of glioma (2, 3).RCAS/tv-a technology relies on somatic gene transfer through infection by RCAS viral vectors derived from the avian retrovirus A (ALV-A) in mice expressing the gene for the RCAS receptor (tv-a). The nestin tv-a (Ntv-a) mouse expresses tv-a under the control of the nestin promoter in glial progenitors. The inherent flexibility of...

P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib

“…U87 forms non-invasive lesions with open vasculature as shown by magnetic resonance imaging (MRI) [25], which explains the 30-fold higher drug levels within the U87 lesion relative to brain adjacent to tumor tissue in the same animal [4]. Similarly, PDGF-B driven models can become very leaky when they develop into high grade tumors, as will likely occur in tumors that also lack Ink4a-Arf [26]. The good accessibility of the tumor cells for the high palbociclib concentration in plasma may cause a further over-estimation of the efficacy of palbociclib.…”

MR Imaging Features of High-Grade Gliomas in Murine Models: How They Compare with Human Disease, Reflect Tumor Biology, and Play a Role in Preclinical Trials

“…1,3,19,32,39,44,45,[50][51][52][53][54][55][56] It is not unusual that drugs that appear very promising in preclinical trials have disappointing clinical results.…”

“…19,39,[44][45][46][51][52][53][54][55][56] Moffat et al 52 compared tumor growth, perfusion parameters, and chemotherapy effectiveness in wild type, VEGF-A overexpressing, and VEGF-A underexpressing 9L gliosarcoma rat xenografts. Perfusion parameters, CBV and CBF, were quantified both by DSC-PWI and continuous arterial spin-labeling and were confronted with MVD and immunohistochemical and genetic analysis by real-time quantitative polymerase chain reaction.…”

“…McConville et al 54 used the Ntv-a GEMM of HGG to appraise the role of conventional MR imaging and DWI in glioma grading and in early prediction of treatment response to temozolomide. MR imaging was able to predict tumor grading among the heterogeneous group of high-and low-grade gliomas generated by this model, treatment response, and survival.…”

Actively decoupled transmit–receive coil‐pair for mouse brain MRI

“…The majority of these animal studies employ mice and the mouse brain has become a particularly important target for the study of a wide variety of diseases, including various white-matter diseases such as Alzheimer’s disease ( 1-3 ), multiple sclerosis ( 4-6 ), and cancer (e.g., high- and low-grade brain tumors) ( 7-9 ). These studies require MR images that provide both high sensitivity (signal-to-noise) and high spatial resolution.…”