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 C(max) 45 microg/ml (277 microM), 73.7 microg/ml (449 microM), and 122 microg/ml (744 microM) 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.
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 C(max) 45 microg/ml (277 microM), 73.7 microg/ml (449 microM), and 122 microg/ml (744 microM) 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.
Authors: Rebecca L Elstrom; Daniel E Bauer; Monica Buzzai; Robyn Karnauskas; Marian H Harris; David R Plas; Hongming Zhuang; Ryan M Cinalli; Abass Alavi; Charles M Rudin; Craig B Thompson Journal: Cancer Res Date: 2004-06-01 Impact factor: 12.701
Authors: Dmitri Dvorzhinski; Anu Thalasila; Paul E Thomas; Deirdre Nelson; Hong Li; Eileen White; Robert S Dipaola Journal: Proteomics Date: 2004-10 Impact factor: 3.984
Authors: Gregory Maschek; Niramol Savaraj; Waldemar Priebe; Paul Braunschweiger; Kara Hamilton; George F Tidmarsh; Linda R De Young; Theodore J Lampidis Journal: Cancer Res Date: 2004-01-01 Impact factor: 12.701
Authors: Murugesan K Gounder; Hongxia Lin; Mark Stein; Susan Goodin; Joseph R Bertino; Ah-Ng Tony Kong; Robert S DiPaola Journal: Biomed Chromatogr Date: 2011-09-19 Impact factor: 1.902
Authors: Ahamed Saleem; Dmitri Dvorzhinski; Urmila Santanam; Robin Mathew; Kevin Bray; Mark Stein; Eileen White; Robert S DiPaola Journal: Prostate Date: 2012-01-12 Impact factor: 4.104
Authors: Frederic A Vallejo; Sumedh S Shah; Nicolas de Cordoba; Winston M Walters; Jeffrey Prince; Ziad Khatib; Ricardo J Komotar; Steven Vanni; Regina M Graham Journal: J Neurooncol Date: 2020-02-24 Impact factor: 4.130