Noninvasive detection of target modulation following phosphatidylinositol 3-kinase inhibition using hyperpolarized 13C magnetic resonance spectroscopy

Christopher S. Ward, Humsa S. Venkatesh, Myriam M. Chaumeil, Alissa H. Brandes, Mark VanCriekinge, Hagit Dafni, Subramaniam Sukumar, Sarah J. Nelson, Daniel B. Vigneron, John Kurhanewicz, C. David James, Daphne A. Haas-Kogan, Sabrina M. Ronen

Research output: Contribution to journalArticlepeer-review

116 Scopus citations

Abstract

Numerous mechanism-based anticancer drugs that target the phosphatidylinositol 3-kinase (PI3K) pathway are in clinical trials. However, it remains challenging to assess responses by traditional imaging methods. Here, we show for the first time the efficacy of hyperpolarized 13C magnetic resonance spectroscopy (MRS) in detecting the effect of PI3K inhibition by monitoring hyperpolarized [1-13C]lactate levels produced from hyperpolarized [1-13C]pyruvate through lactate dehydrogenase (LDH) activity. In GS-2 glioblastoma cells, PI3K inhibition by LY294002 or everolimus caused hyperpolarized lactate to drop to 42 ± 12% and to 76 ± 5%, respectively. In MDA-MB-231 breast cancer cells, hyperpolarized lactate dropped to 71 ± 15% after treatment with LY294002. These reductions were correlated with reductions in LDH activity to 48 ± 4%, 63 ± 4%, and 69 ± 12%, respectively, and were associated with a drop in levels of LDHA mRNA and LDHA and hypoxia-inducible factor-1α proteins. Supporting these findings, tumor growth inhibition achieved by everolimus in murine GS-2 xenografts was associated with a drop in the hyperpolarized lactate-to-pyruvate ratio detected by in vivo MRS imaging, whereas an increase in this ratio occurred with tumor growth in control animals. Taken together, our findings illustrate the application of hyperpolarized 13C MRS of pyruvate to monitor alterations in LDHA activity and expression caused by PI3K pathway inhibition, showing the potential of this method for noninvasive imaging of drug target modulation.

Original languageEnglish (US)
Pages (from-to)1296-1305
Number of pages10
JournalCancer Research
Volume70
Issue number4
DOIs
StatePublished - Feb 15 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Noninvasive detection of target modulation following phosphatidylinositol 3-kinase inhibition using hyperpolarized <sup>13</sup>C magnetic resonance spectroscopy'. Together they form a unique fingerprint.

Cite this