Use of a Luciferase-Expressing Orthotopic Rat Brain Tumor Model to Optimize a Targeted Irradiation Strategy for Efficacy Testing with Temozolomide

Abstract

Glioblastoma multiforme (GBM) is a common and aggressive malignant brain cancer with a mean survival time of approximately 15 months after initial diagnosis. Currently, the standard-of-care (SOC) treatment for this disease consists of radiotherapy (RT) with concomitant and adjuvant temozolomide (TMZ). We sought to develop an orthotopic preclinical model of GBM and to optimize a protocol for non-invasive monitoring of tumor growth, allowing for determination of the efficacy of SOC therapy using a targeted RT strategy combined with TMZ. A strong correlation (r = 0.80) was observed between contrast-enhanced (CE)-CT-based volume quantification and bioluminescent (BLI)-integrated image intensity when monitoring tumor growth, allowing for BLI imaging as a substitute for CE-CT. An optimized parallel-opposed single-angle RT beam plan delivered on average 96% of the expected RT dose (20, 30 or 60 Gy) to the tumor. Normal tissue on the ipsilateral and contralateral sides of the brain were spared 84% and 99% of the expected dose, respectively. An increase in median survival time was demonstrated for all SOC regimens compared to untreated controls (average 5.2 days, p < 0.05), but treatment was not curative, suggesting the need for novel treatment options to increase therapeutic efficacy.

Non-Invasive Evaluation of Acute Effects of Tubulin Binding Agents: A Review of Imaging Vascular Disruption in Tumors

“…Dynamic BLI is very effective for initial evaluation of potential VDAs, providing high throughput results with relative ease and low cost. There are distinct limitations, though many are readily overcome: (i) requires transfected cells to express luciferase effectively (many stably transfected cell lines are now available); (ii) requires administration of luciferin substrate (currently readily available, cheap and non-toxic); (iii) requires optical imaging system (typically cheapest of all available modalities); (iv) typically limited to mice due to light scattering by tissues, although BLI has been reported in rats including prostate [ 198 ], brain [ 178 , 213 ] and lung tumors [ 214 ]. Other more sophisticated technologies provide alternative imaging approaches.…”

A deep learning and Monte Carlo based framework for bioluminescence imaging center of mass-guided glioblastoma targeting

“…The starting point of this study was previous in vivo experiments of an F98 rat orthotopic glioma model (Mowday et al 2020). Contrast-enhanced CBCT (CE-CBCT) images, with 0.1 mm resolution in all directions, were acquired at different time points in a tumor-growth study from 35 different animals resulting in 57 images in total.…”

“…Tumor cells are the only bioluminescence light emitter inside the animal resulting in an almost zero background signal. Thus, the total number of detected photons correlates linearly with the tumor volume (Deng et al 2020, Mowday et al 2020. Therefore, tumor volume can be estimated by performing logistic regression between the total number of surface photon counts and the tumor volume in the training database.…”

Mismatch between Bioluminescence Imaging (BLI) and MRI When Evaluating Glioblastoma Growth: Lessons from a Study Where BLI Suggested “Regression” while MRI Showed “Progression”

“…Due to the localization within the cranial cavity, the evolution of tumor growth (or regression) of GBM models can only be monitored thanks to noninvasive imaging. Noninvasive techniques make longitudinal studies possible, require fewer animals, and have greater statistical power thanks to the use of animals as their own controls [ 5 ]. Most studies on rodent models of GBM have used magnetic resonance imaging (MRI), contrast-enhanced CT [ 6 ], or bioluminescence imaging (BLI).…”