Phospholipid Metabolites in Recurrent Glioblastoma: In Vivo Markers Detect Different Tumor Phenotypes before and under Antiangiogenic Therapy

Abstract

PurposeMetabolic changes upon antiangiogenic therapy of recurrent glioblastomas (rGBMs) may provide new biomarkers for treatment efficacy. Since in vitro models showed that phospholipid membrane metabolism provides specific information on tumor growth we employed in-vivo MR-spectroscopic imaging (MRSI) of human rGBMs before and under bevacizumab (BVZ) to measure concentrations of phosphocholine (PCho), phosphoethanolamine (PEth), glycerophosphocholine (GPC), and glyceroethanolamine (GPE).Methods 1H and 31P MRSI was prospectively performed in 32 patients with rGBMs before and under BVZ therapy at 8 weeks intervals until tumor progression. Patients were dichotomized into subjects with long overall survival (OS) (>median OS) and short OS (<median OS) survival time from BVZ-onset. Metabolite concentrations from tumor tissue and their ratios were compared to contralateral normal-appearing tissue (control).ResultsBefore BVZ, 1H-detectable choline signals (total GPC and PCho) in rGBMs were elevated but significance failed after dichotomizing. For metabolite ratios obtained by 31P MRSI, the short-OS group showed higher PCho/GPC (p = 0.004) in rGBMs compared to control tissue before BVZ while PEth/GPE was elevated in rGBMs of both groups (long-OS p = 0.04; short-OS p = 0.003). Under BVZ, PCho/GPC and PEth/GPE in the tumor initially decreased (p = 0.04) but only PCho/GPC re-increased upon tumor progression (p = 0.02). Intriguingly, in normal-appearing tissue an initial PEth/GPE decrease (p = 0.047) was followed by an increase at the time of tumor progression (p = 0.031).ConclusionAn elevated PCho/GPC ratio in the short-OS group suggests that it is a negative predictive marker for BVZ efficacy. These gliomas may represent a malignant phenotype even growing under anti-VEGF treatment. Elevated PEth/GPE may represent an in-vivo biomarker more sensitive to GBM infiltration than MRI.

IDH1 R132H Mutation Generates a Distinct Phospholipid Metabolite Profile in Glioma

“…For all tumors in the mouse brain, we detected a decreased PCr/ATP ratio, which is in line with findings in 31 P MRS of human tumors and indicates an altered energy metabolism (37,50).…”

“…Because 31 P MRS is less sensitive than 1 H MRS and requires dedicated radiofrequency probes, it has been less used to examine phospholipid metabolites in vivo in brain tumors (36,37). However, the increased access to high-field (pre-) clinical MR scanners, which improves 31 P MRS sensitivity and resolution, invigorates its further exploration in studies of tumor phospholipid metabolism.…”

Intratumoral Concentrations and Effects of Orally Administered Micellar Curcuminoids in Glioblastoma Patients

“…P MRSI was performed as described elsewhere (24,25). Briefly, MRSI of the brain was performed on a 3-T whole-body system (Magnetom Trio, Siemens Medical AG, Erlangen, Germany) using a double-tuned 1 H/ 31 P volume head coil (Rapid Biomedical, W€ urzburg, Germany).…”

Auf dem Weg zu mehr Präzision in der Hirntumortherapie

“…Phosphorverbindungen spielen eine große Rolle im Metabolismus gesunder und neoplastischer Zellen. Auch wenn die Erhöhung bestimmter phosphorylierter Membranmetabolite in vitro mit neoplastischer Aktivität korrelierte, müssen erste vielversprechende In-vivo-Ergebnisse noch validiert werden [20,21].…”