Evaluating Magnetic Resonance Spectroscopy as a Tool for Monitoring Therapeutic Response of Whole Brain Radiotherapy in a Mouse Model for Breast-to-Brain Metastasis

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.

The immune suppressive microenvironment affects efficacy of radio‐immunotherapy in brain metastasis

“…Given recent reports on immune modulatory effects of ionizing radiation (IR), we evaluated effects of radiotherapy on the BrM TME. IR was applied as fractionated whole brain radiotherapy with 2 Gy on five consecutive days (5 × 2 Gy) in 1 arc using the Small Animal Radiation Research Platform (SARRP) (Wong et al, 2008) as previously described (Chae et al, 2019). Treatment was commenced when animals developed established metastatic lesions based on magnetic resonance imaging (MRI) (Fig 4A and B).…”

“…BrM progression was monitored by MRI measurements until the trial end point. MRI was performed using a 7 Tesla Small Animal MR Scanner (PharmaScan, Bruker) with a volume coil as transmitter and a head surface coil for signal reception as previously described (Chae et al, 2019). Mice were injected intraperitoneally (i.p.)…”

“…The 99LN cell line was derived from a metastatic lymph node of the MMTV-PyMT breast cancer model (C57Bl6/J background) and selected in vivo for brain homing capacity as previously described (Bowman et al, 2016), resulting in the 99LN-BrM2 variant used herein (Chae et al, 2019). The TS1 cell line was derived from primary tumors of the MMTV-PyMT breast cancer model (FVB/n background) as previously described (Shree et al, 2011), and brain metastatic variants were selected as previously described (Sevenich et al, 2014).…”

“…This indicates that immune modulation in BrM has the potential to overcome resistance to ICB. Given recent reports on synergistic anti‐tumor effects of radio‐immunotherapy (Koller et al, 2017) and the accumulating evidence that radiation can be used as an immune modulatory agent (Rodriguez‐Ruiz et al, 2018; Sevenich, 2019; Schulz et al, 2020), we sought to evaluate the efficacy of radio‐immunotherapy in the syngeneic breast‐to‐brain metastasis model 99LN‐BrM (Bowman et al, 2016; Chae et al, 2019) with a particular focus on immune modulation induced by whole brain radiotherapy (WBRT) alone and in combination with ICB. Here, we show that WBRT sensitizes BrM to ICB by increasing the relative abundance of CD8 + T cells and by preventing the establishment of lymphoid cell‐mediated immune suppressive effects.…”

Hippocampal changes in inflammasomes, apoptosis, and MEMRI after radiation-induced brain injury in juvenile rats

“…Magnetic resonance spectroscopy (MRS) is another imaging method that can be used to detect metabolic changes in the hippocampus in a noninvasive manner [21]. MRS can be used to monitor brain tumor progression and is helpful for identifying radiation necrosis after radiation therapy [22,23]. In studies of radiation brain damage, MRS has been shown to detect early metabolic changes in normal irradiated brain tissue [24][25][26].…”