Abstract
Brain metastases are the most common intracranial tumor in adults and are associated with poor patient prognosis and median survival of only a few months. Treatment options for brain metastasis patients remain limited and largely depend on surgical resection, radio- and/or chemotherapy. The development and pre-clinical testing of novel therapeutic strategies require reliable experimental models and diagnostic tools that closely mimic technologies that are used in the clinic and reflect histopathological and biochemical changes that distinguish tumor progression from therapeutic response. In this study, we sought to test the applicability of magnetic resonance (MR) spectroscopy in combination with MR imaging to closely monitor therapeutic efficacy in a breast-to-brain metastasis model. Given the importance of radiotherapy as the standard of care for the majority of brain metastases patients, we chose to monitor the post-irradiation response by magnetic resonance spectroscopy (MRS) in combination with MR imaging (MRI) using a 7 Tesla small animal scanner. Radiation was applied as whole brain radiotherapy (WBRT) using the image-guided Small Animal Radiation Research Platform (SARRP). Here we describe alterations in different metabolites, including creatine and N-acetylaspartate, that are characteristic for brain metastases progression and lactate, which indicates hypoxia, while choline levels remained stable. Radiotherapy resulted in normalization of metabolite levels indicating tumor stasis or regression in response to treatment. Our data indicate that the use of MR spectroscopy in addition to MRI represents a valuable tool to closely monitor not only volumetrical but also metabolic changes during tumor progression and to evaluate therapeutic efficacy of intervention strategies. Adapting the analytical technology in brain metastasis models to those used in clinical settings will increase the translational significance of experimental evaluation and thus contribute to the advancement of pre-clinical assessment of novel therapeutic strategies to improve treatment options for brain metastases patients.
Highlights
Brain metastases are the most common brain tumor in adults with an incidence of 10 per 100,000 population across all tumor types [1]
Tumor progression could be followed for 12–15 weeks after tumor cell inoculation, a time point at which most animals developed symptoms characterized by neurological deficits including head tilts and disequilibrium
Data obtained by MR spectroscopy revealed a pronounced reduction of total NAA and total creatine as well as a significant increase in lactate levels in untreated 99LN-brain metastatic (BrM)-bearing mice, while total choline levels remained stable over time
Summary
Brain metastases are the most common brain tumor in adults with an incidence of 10 per 100,000 population across all tumor types [1]. Pre-clinical research represents an important part of the effort to improve treatment option by allowing mechanistic insight into cellular and molecular drivers of tumor progression and by providing platforms to test the efficacy of novel therapeutic avenues For this purpose, experimental tumor models and adequate technological tools are required to mimic the clinical situation as closely as possible and improve the quality and translational significance of preclinical research [24, 25]. We demonstrate that MR spectroscopy in combination with MR imaging represents a valuable tool for non-invasive monitoring of parameters that reflect tumor progression or regression and provide detailed insight into the histopathological and metabolic status of brain metastases to evaluate therapeutic efficacy over time in a preclinical model
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