MR Studies of Glioblastoma Models Treated with Dual PI3K/mTOR Inhibitor and Temozolomide:Metabolic Changes Are Associated with Enhanced Survival

Abstract

Current standard of care for glioblastoma (GBM) is surgical resection, radiation, and treatment with Temozolomide (TMZ). However, resistance to current therapies and recurrence are common. To improve survival, agents that target the phosphoinositide-3-kinase (PI3K) signaling pathway, which is activated in ∼88% of GBM, are currently in clinical trials. A challenge with such therapies is that tumor shrinkage is not always observed. New imaging methods are therefore needed to monitor response to therapy and predict survival. The goal of this study was to determine whether hyperpolarized 13C magnetic resonance spectroscopic imaging (MRSI) and 1H magnetic resonance spectroscopy (MRS) can be used to monitor response to the second-generation dual PI3K/mTOR inhibitor voxtalisib (XL765, SAR245409), alone or in combination with TMZ. We investigated GS-2 and U87-MG GBM orthotopic tumors in mice, and used magnetic resonance imaging (MRI), hyperpolarized 13C MRSI and 1H MRS to monitor the effects of treatment. In our study, 1H MRS could not predict tumor response to therapy. However, in both our models, we observed a significantly lower hyperpolarized lactate-to-pyruvate ratio in animals treated with voxtalisib, TMZ, or combination therapy, when compared to controls. This metabolic alteration was observed prior to MRI-detectable changes in tumor size, was consistent with drug-action, and was associated with enhanced animal survival. Our findings confirm the potential translational value of the hyperpolarized lactate-to-pyruvate ratio as a biomarker for noninvasively assessing the effects of emerging therapies for patients with GBM.

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

“…A decrease in hyperpolarized [1- 13 C]-lactate/[1- 13 C]-pyruvate ratio was correlated with a drop in LDHA expression and HIF-1α activity in response to Everolimus, a first-generation mTOR inhibitor, and in response to LY294002, a PI3K inhibitor, in GS-2 GBM cells 37,67 and in a GS-2 rat orthotopic tumor model 73 . A similar observation was made following treatment with Voxtalisib, a second-generation dual PI3K/mTOR inhibitor in GS-2 and U87 GBM models in mice 70 . In response to treatment with Temozolomide (TMZ), the current standard of care for GBM, a decrease in pyruvate kinase M2 (PKM2) in orthotopic U87 and GS-2 GBM models in rats also led to a decrease in hyperpolarized [1- 13 C]-lactate production 70,75,76 .…”

“…A similar observation was made following treatment with Voxtalisib, a second-generation dual PI3K/mTOR inhibitor in GS-2 and U87 GBM models in mice 70 . In response to treatment with Temozolomide (TMZ), the current standard of care for GBM, a decrease in pyruvate kinase M2 (PKM2) in orthotopic U87 and GS-2 GBM models in rats also led to a decrease in hyperpolarized [1- 13 C]-lactate production 70,75,76 . Importantly, a drop in hyperpolarized [1- 13 C]-lactate production in all these models was an early event that occurred prior to tumor shrinkage and was associated with increased animal survival.…”

“…Briefly, dynamic data sets from live cells have been obtained by acquiring sequential spectra using a pulse-acquire sequence with a low flip angle 57,67–69 . In vivo animal brain tumor studies have been performed using either dynamic or single time point 2D chemical shift imaging (CSI) with low flip angle 70,71 . An alternate approach used is single time point 2D MR spectroscopic imaging using a double spin echo RF pulse with variable flip angles 72,73 (see Tables 1 and 2).…”

“…Elevated hyperpolarized [1- 13 C]-lactate production following the injection of hyperpolarized [1- 13 C]-pyruvate was detected in several preclinical orthotopic GBM models compared to normal brain 67,70,72-74 . In contrast, in a low-grade IDH1 mutant orthotopic tumor model where LDHA is silenced 42 , very low production of hyperpolarized [1- 13 C]-lactate was observed 69 .…”

Hyperpolarized 13 C pyruvate mouse brain metabolism with absorptive-mode EPSI at 1 T

“…Extending this work to mouse brain tumor models permits application to a wider array of pre-clinical models and the use of newly synthesized hyperpolarized probes, as recently demonstrated [11–13]. Imaging the smaller mouse brain however presents unique challenges.…”