Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies.
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.
Stein
Mark
M
Cancer Institute of New Jersey, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, New Jersey 08901, USA. steinmn@umdnj.edu
Lin
Hongxia
H
Jeyamohan
Chandrika
C
Dvorzhinski
Dmitri
D
Gounder
Murugesan
M
Bray
Kevin
K
Eddy
Simantini
S
Goodin
Susan
S
White
Eileen
E
Dipaola
Robert S
RS
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019540:Area Under Curve; D003847:Deoxyglucose / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018579:Patient Selection; D049268:Positron-Emission Tomography; D011471:Prostatic Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D002583:Uterine Cervical Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000378:metabolism
D003847:Deoxyglucose