HDAC inhibition in glioblastoma monitored by hyperpolarized ¹³C MRSI

Abstract

Vorinostat is a histone deacetylase (HDAC) inhibitor that inhibits cell proliferation and induces apoptosis in solid tumors, and is in clinical trials for the treatment of glioblastoma (GBM). The goal of this study was to assess whether hyperpolarized 13C MRS and magnetic resonance spectroscopic imaging (MRSI) can detect HDAC inhibition in GBM models. First, we confirmed HDAC inhibition in U87 GBM cells and evaluated real‐time dynamic metabolic changes using a bioreactor system with live vorinostat‐treated or control cells. We found a significant 40% decrease in the 13C MRS‐detectable ratio of hyperpolarized [1‐13C]lactate to hyperpolarized [1‐13C]pyruvate, [1‐13C]Lac/Pyr, and a 37% decrease in the pseudo‐rate constant, kPL, for hyperpolarized [1‐13C]lactate production, in vorinostat‐treated cells compared with controls. To understand the underlying mechanism for this finding, we assessed the expression and activity of lactate dehydrogenase (LDH) (which catalyzes the pyruvate to lactate conversion), its associated cofactor nicotinamide adenine dinucleotide, the expression of monocarboxylate transporters (MCTs) MCT1 and MCT4 (which shuttle pyruvate and lactate in and out of the cell) and intracellular lactate levels. We found that the most likely explanation for our finding that hyperpolarized lactate is reduced in treated cells is a 30% reduction in intracellular lactate levels that occurs as a result of increased expression of both MCT1 and MCT4 in vorinostat‐treated cells. In vivo 13C MRSI studies of orthotopic tumors in mice also showed a significant 52% decrease in hyperpolarized [1‐13C]Lac/Pyr when comparing vorinostat‐treated U87 GBM tumors with controls, and, as in the cell studies, this metabolic finding was associated with increased MCT1 and MCT4 expression in HDAC‐inhibited tumors. Thus, the 13C MRSI‐detectable decrease in hyperpolarized [1‐13C]lactate production could serve as a biomarker of response to HDAC inhibitors.

MR-detectable metabolic biomarkers of response to mutant IDH inhibition in low-grade glioma

“…Most notably, hyperpolarized [1- 13 C] pyruvate and [2- 13 C] pyruvate are currently in clinical trials for glioma patients 20 , 74 . Additionally, multiple earlier studies with different chemotherapeutic agents and targeted therapies have used hyperpolarized [1- 13 C] pyruvate in animal models as well as in prostate cancer patients and have shown that a drop in its flux to lactate is associated with response to therapy 19 , 75 - 79 . However, as shown in this study, the utility of pyruvate to assess response to mutant IDH1 inhibitors is likely to be limited ( Figure S2 ).…”

Hyperpolarized Pyruvate MR Spectroscopy Depicts Glycolytic Inhibition in a Mouse Model of Glioma

“…Importantly, the changes in cancer metabolism depicted at hyperpolarized pyruvate MR spectroscopy reflect the real-time glycolytic state of tumors and precede morphologic changes observed at T2-weighted imaging (8,14). This technology therefore holds promise to provide early indications of response in glioma (19) after treatment with radiation therapy (5), chemotherapy (7,9), and immunotherapy. Hyperpolarized pyruvate MR spectroscopy measurements are particularly well suited for depicting the effects of emerging metabolic therapies for glioma, such as inhibitors of glycolytic and mitochondrial metabolism (20).…”

“…Dissolution dynamic nuclear polarization can enhance the MRI signal of [1-carbon 13 { 13 C}]-pyruvate more than 10 000 fold compared with thermal equilibrium, enabling new insights into tumor metabolism in vivo (4). Previous work in rodent models of glioma has demonstrated that hyperpolarized [1-13 C]-pyruvate MR spectroscopy depicts decreases in tumor lactate metabolism caused by radiation therapy (5) and chemotherapy (6)(7)(8)(9) within a few days of treatment. Recent advances in hyperpolarized 13 C MRI have enabled the real-time measurement of glycolytic metabolism in patients with brain cancer (10,11).…”

Imaging toxin-induced neuroinflammation in mice using hyperpolarized13C magnetic resonance spectroscopy

“…45 showed increased lactate production in the heart following a myocardial infarction, which was normalized following monocyte/macrophage depletion. Future bioreactor studies 46 of the individual cell types could also be valuable to decipher the contributions of specific cell types. Only a few HP studies have been carried out on a preclinical, murine-dedicated, cryogen-free 3 Tesla system 47,48 .…”