MR Molecular Imaging of Brain Cancer Metabolism Using Hyperpolarized 13C Magnetic Resonance Spectroscopy

Abstract

Metabolic reprogramming is an important hallmark of cancer. Alterations in many metabolic pathways support the requirement for cellular building blocks that are essential for cancer cell proliferation. This metabolic reprogramming can be imaged using magnetic resonance spectroscopy (MRS). 1H MRS can inform on alterations in the steady-state levels of cellular metabolites, but the emergence of hyperpolarized 13C MRS has now also enabled imaging of metabolic fluxes in real-time, providing a new method for tumor detection and monitoring of therapeutic response. In the case of glioma, preclinical cell and animal studies have shown that the hyperpolarized 13C MRS metabolic imaging signature is specific to tumor type and can distinguish between mutant IDH1 glioma and primary glioblastoma. Here, we review these findings, first describing the main metabolic pathways that are altered in the different glioma subtypes, and then reporting on the use of hyperpolarized 13C MRS and MR spectroscopic imaging (MRSI) to probe these pathways. We show that the future translation of this hyperpolarized 13C MRS molecular metabolic imaging method to the clinic promises to improve the noninvasive detection, characterization, and response-monitoring of brain tumors resulting in improved patient diagnosis and clinical management.

HDAC inhibition in glioblastoma monitored by hyperpolarized 13C MRSI

“…Most notably, monitoring the conversion of hyperpolarized [1‐ 13 C]pyruvate to hyperpolarized [1‐ 13 C]lactate has recently been implemented in the clinic . Importantly, previous studies have shown that this metabolic reaction can serve as an early biomarker of response to therapy in a range of tumor types, including in orthotopic intracranial GBM models . However, the effect of HDAC inhibitors had not been previously investigated using this emerging imaging method.…”

“…24,25,38 Importantly, previous studies have shown that this metabolic reaction can serve as an early biomarker of response to therapy in a range of tumor types, including in orthotopic intracranial GBM models. 17,18,20,21,38,39 However, the effect of HDAC inhibitors had not been previously investigated using this emerging imaging method. In this study we therefore investigated HDAC inhibition by vorinostat in a GBM model, performing studies first in live cells and then in vivo in orthotopic GBM tumors in mice.…”

“…[40][41][42][43] The observation that GBM response to vorinostat treatment is associated with a significant drop in hyperpolarized [1-13 C]lactate production is similar to the findings in a range of tumor types, in which response to both chemotherapy and targeted therapies led to a drop in [1-13 C]lactate production. 16,17 Since our in vivo studies use a CSI sequence, partial volume effects could be a concern. However, it should be noted that our maximum gradient strength is 1000 mT/cm.…”

“…Importantly, metabolic imaging using hyperpolarized 13 C MRSI has been shown to provide an early metabolic biomarker of tumor response to treatment in a range of tumor types. 16,17 In the case of GBM, our group and others have shown the value of probing the metabolism of pyruvate to lactate for detection of the efficacy of TMZ, everolimus (an mTOR inhibitor) and voxtalisib (a dual PI3K/mTOR inhibitor), in cells and in vivo in orthotopic rodent models. Following a single dose of TMZ, a tumor-bearing rat demonstrated a significant drop in hyperpolarized [1-13 C]lactate production from hyperpolarized [1-13 C]pyruvate prior to changes in tumor volume.…”

“…This recent technological development improves the signal‐to‐noise ratio of 13 C‐containing molecules by more than 10 000‐fold, allowing monitoring of metabolic fluxes in real time not only in vitro but also noninvasively in vivo . Importantly, metabolic imaging using hyperpolarized 13 C MRSI has been shown to provide an early metabolic biomarker of tumor response to treatment in a range of tumor types . In the case of GBM, our group and others have shown the value of probing the metabolism of pyruvate to lactate for detection of the efficacy of TMZ, everolimus (an mTOR inhibitor) and voxtalisib (a dual PI3K/mTOR inhibitor), in cells and in vivo in orthotopic rodent models.…”