Reduced phosphocholine and hyperpolarized lactate provide magnetic resonance biomarkers of PI3K/Akt/mTOR inhibition in glioblastoma

Humsa S. Venkatesh, Myriam M. Chaumeil, Christopher S. Ward, Daphne A. Haas-Kogan, C. David James, Sabrina M. Ronen*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

71 Scopus citations

Abstract

The phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway is activated in more than88 of glioblastomas (GBM). New drugs targeting this pathway are currently in clinical trials. However, noninvasive assessment of treatment response remains challenging. By using magnetic resonance spectroscopy (MRS), PI3K/Akt/mTOR pathway inhibition was monitored in 3 GBM cell lines (GS-2, GBM8, and GBM6; each with a distinct pathway activating mutation) through the measurement of 2 mechanistically linked MR biomarkers: phosphocholine (PC) and hyperpolarized lactate. 31P MRS studies showed that treatment with the PI3K inhibitor LY294002 induced significant decreases in PC to 34 ± 9 of control in GS-2 cells, 48 ± 5 in GBM8, and 45 ± 4 in GBM6. The mTOR inhibitor everolimus also induced a significant decrease in PC to 62 ± 14, 57 ± 1, and 58 ± 1 in GS-2, GBM8, and GBM6 cells, respectively. Using hyperpolarized 13C MRS, we demonstrated that hyperpolarized lactate levels were significantly decreased following PI3K/Akt/mTOR pathway inhibition in all 3 cell lines to 51 ± 10, 62 ± 3, and 58 ± 2 of control with LY294002 and 72 ± 3, 61 ± 2, and 66 ± 3 of control with everolimus in GS-2, GBM8, and GBM6 cells, respectively. These effects were mediated by decreases in the activity and expression of choline kinase α and lactate dehydrogenase, which respectively control PC and lactate production downstream of HIF-1. Treatment with the DNA damaging agent temozolomide did not have an effect on either biomarker in any cell line. This study highlights the potential of PC and hyperpolarized lactate as noninvasive MR biomarkers of response to targeted inhibitors in GBM.

Original languageEnglish (US)
Pages (from-to)315-325
Number of pages11
JournalNeuro-oncology
Volume14
Issue number3
DOIs
StatePublished - Mar 2012

Keywords

  • PI3K/Akt/mTOR pathway
  • glioblastoma (GBM)
  • hyperpolarized lactate
  • magnetic resonance spectroscopy (MRS)
  • phosphocholine (PC)

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

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