Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies

Mark Stein, Hongxia Lin, Chandrika Jeyamohan, Dmitri Dvorzhinski, Murugesan Gounder, Kevin Bray, Simantini Eddy, Susan Goodin, Eileen White, Robert S. Dipaola

Research output: Contribution to journalArticlepeer-review

161 Scopus citations

Abstract

BACKGROUND A profound difference between cancer and normal tissues is the preferential utilization of glycolysis by cancer cells. To translate this paradigm in the clinic, we completed a phase I study of 2-deoxyglucose (2DG), and assessed 2DG uptake with fluorodeoxyglucose (FDG) positron emission tomography (PET) and the autophagy substrate p62 as a marker of 2DG resistance. METHODS Patients received 2DG orally on days 1-14 of a 21-day cycle in cohorts of three in a dose-escalating manner. Correlative assessments included PET scans at baseline and day 2 and p62 protein in peripheral blood mononuclear cells as a potential marker of 2DG resistance. RESULTS The dose of 45 mg/kg was defined as the recommended phase II dose, secondary to dose-limiting toxicity of grade 3 asymptomatic QTc prolongation at a dose of 60 mg/kg. PK evaluation of 2DG revealed linear pharmacokinetics with Cmax 45 μg/ml (277 μM), 73.7 μg/ml (449 μM), and 122 μg/ml (744 μM) in dose levels 30, 45, and 60 mg/kg, respectively. Five of eight patients assessed with FDG-PET scanning demonstrated decreased FDG uptake by day 2 of therapy, suggesting competition of 2DG with FDG. Five of six patients assessed for p62 had a decrease in p62 at 24 hr. CONCLUSIONS These data support the safety of 2DG, defined 2DG PK, demonstrated the effect of 2DG on FDG-PET imaging, and demonstrated the feasibility of assessment of p62 as an autophagic resistance marker. These data support future studies of 2DG alone or in combination with approaches to abrogate autophagy. Prostate 70: 1388-1394, 2010.

Original languageEnglish (US)
Pages (from-to)1388-1394
Number of pages7
JournalProstate
Volume70
Issue number13
DOIs
StatePublished - Sep 15 2010

All Science Journal Classification (ASJC) codes

  • Oncology
  • Urology

Keywords

  • Autophagy
  • Deoxyglucose
  • Metabolism
  • P62
  • Prostate cancer

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