Hyperpolarized Pyruvate MRI to Characterize Glioma Metabolism Non-invasively in Man

Lay Summary

MRI “metabolic” imaging may quickly show if a brain tumor is recurring or responding to treatment

A new type of MRI imaging that reflects the metabolism of brain tumor cells versus that of healthy brain cells may serve as an early biomarker of whether a tumor treatment is working.

Aggressive brain tumors, called gliomas, can be potentially deadly within about a year, so it is essential to determine as early as possible whether a particular treatment is working or an alternative should be tried. Treatment usually begins with surgery to remove as much of the tumor as possible, followed by radiation and drugs. Immunotherapies are also now being used to try to bolster the body’s own immune system to kill tumor cells and prevent new ones from emerging.

The main problem, though, is that it takes a while with current imaging to see whether the treatment is working or should be replaced with an alternative. Imaging cannot differentiate masses of radiation-killed brain cells from active tumor cell masses; nor can imaging differentiate brain swelling (edema) produced by the tumor versus edema produced by the brain’s positive inflammatory response against the tumor.

A new MRI technique, however, may change all that. The technique is based on the fact that the metabolism of rapidly dividing tumor cells differs from that of healthy brain cells. In breaking down sugar (brain glucose) for energy, tumor cells convert a metabolite called pyruvate into lactate, while healthy brain cells convert pyruvate into bicarbonate. This difference is exploited by a new imaging technique called “hyperpolarized MR Spectroscopy.”

Pyruvate that is “hyperpolarized” sends a strong signal that can be detected by MR spectroscopy after it is administered intravenously into the patient’s bloodstream. Brain tumor cells convert the pyruvate into lactate, and MR Spectroscopy can detect where—and how much—lactate there is in the brain. Like PET, this MRI technique can show metabolic activity but without PET’s need to use radioactive tracers. So hyperpolarized MR Spectroscopy can be performed safely a few times during a short time period to determine if the patient’s tumor is progressing (more lactate) or the treatment is working (less lactate).

This technique is currently being tested to assess prostate cancer treatments, and initial evidence suggests it provides accurate results. The investigators recently obtained pivotal evidence that that hyperpolarized pyruvate gets past the blood brain barrier into the brain, and they hypothesize that it will be a valid measure of treatment is working early in the treatment’s course. They will test this hypothesis in 25 patients with glioma. Investigators will determine the technique’s validity in detecting tumor and its recurrence by comparing the results of MR Spectroscopy with studies of patients’ brain tissue, clinical outcomes, and with results of other types of imaging.

Significance: Hyperpolarized MR Spectroscopy may become the first biomarker for early assessment of whether a glioma treatment is working or should be changed.

Abstract

Hyperpolarized Pyruvate MRI to Characterize Glioma Metabolism Non-invasively in Man

Hypothesis: The novel hyperpolarized MRI (HP MRI) method using hyperpolarized [1-13C] pyruvate can detect the abnormal metabolism of active high-grade gliomas. We expect active tumor metabolism to differ significantly from treatment related changes, and serve as an imaging biomarker of active tumor in the post-treatment setting. Analogous to pre-clinical models, active tumor should demonstrate increased production of lactate with increased kinetics compared to normal brain. Relevance: Standard brain imaging techniques cannot accurately differentiate between active tumor and treatment related changes in the post-therapeutic setting. Increased enhancement, mass effect, and edema due to inflammatory changes can mimic active tumor, called pseudoprogression. Alternatively, subsiding enhancement and edema may mimic tumor response, called pseudoresponse. Differentiating these possibilities and quantifying the amount of residual tumor remains an open-problem in neuroradiology, often presenting a clinical dilemma. Furthermore, the inability to differentiate between tumor and treatment effect is becoming increasingly important as new immune-modulatory treatments (i.e. vaccine trials, check-point inhibitors) or metabolically targeted treatments (i.e., IDH1 inhibitors) are being developed. Our proposal aims to implement HP MRI to improve the specificity of standard imaging. Hyperpolarized MRI is an entirely different technology, ideally suited to image in vivo metabolism by dramatically amplifying the MR signal from small molecules central to endogenous metabolic processes. The signal increase, on the order of 10,000 fold, allows sensitivity to metabolites at micro-to-nano molar concentrations (1) (2). The most widespread hyperpolarization method (Dissolution Dynamic Nuclear Polarization) is applied to small molecules that are hyperpolarized ex vivo, and subsequently administered intravenously, similar to contrast agents, although with emergent properties as metabolic biomarkers (3). Of the many potential applications of HP metabolic probes, oncological applications are a primary target because the metabolism of active tumor cells is known to be significantly different from normal, quiescent or necrotic cells (4). The inherent spectral resolution of MRI can distinguish substrates from multiple downstream metabolic products and quantify the kinetics of active metabolism in real time. Hyperpolarized [1-13C] pyruvate (HP pyruvate) is emerging as a canonical tracer of reductive glycolysis. The preferential metabolism of HP pyruvate to lactate has been shown in pre-clinical animal models of glioma and first-in-human studies have demonstrated the application and safety of HP pyruvate metabolic imaging. The application of hyperpolarized metabolic imaging to brain tumors would represent a significant advancement in neuro-oncological imaging. The promise is a definitive and robust method to differentiate recurrence from treatment response in brain tumors, with far-reaching consequences for developing advances in clinical practice, and our fundamental understanding of the brain. Aims: With our preliminary feasibility data in hand, we aim to conduct a first-in-human hyperpolarized brain MRI study and test the ability of hyperpolarized pyruvate imaging to detect abnormal tumor metabolism in a total of 25 patients (50 imaging sessions). In Aim 1 we will assess reproducibility and optimize our imaging strategy. We will image 5 patients dynamically (2 injections per patient), capturing time-dependent kinetics of pyruvate to lactate metabolism. This dynamic information will then be used to choose an appropriate time-point for high-resolution 3D. In Aim 2 we will apply high-resolution 3D imaging to 20 patients in the pre-operative and post-therapeutic settings to determine metabolic profiles of the native tumor, and treatment effects versus recurrence. We will comprehensively correlate our quantitative metabolic profiles with additional imaging features, histological markers, and patient outcomes. Methods: This is a multi-disciplinary project, bridging the science of cancer metabolism, magnetic resonance imaging physics, neuro-oncology and neurosurgery. Our proposal is centered on a novel imaging technology primed to detect the abnormal metabolism of active tumor cells. Patient recruitment will be performed in accordance with an actively accruing institutional review board approved trial for hyperpolarized metabolic imaging. Hyperpolarization of [1-13C] pyruvate will be accomplished by the dissolution dynamic nuclear polarization (DNP) method, using a clinical SpinLab Hyperpolarizer. Following injection of the hyperpolarized sample, the pyruvate substrate and the immediate metabolic products (lactate and bicarbonate) will be imaged with a magnetic resonance spectroscopic imaging sequence (MRSI) using dedicated 13C excitation/acquisition hardware.