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

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.

Combination of glycolysis inhibition with chemotherapy results in an antitumor immune response

“…Our study suggests that such cotreatment might be efficient not only by increasing the cytotoxicity of the chemotherapy but also by allowing the immune system to react against the tumor. It is interesting to note that the dose of 2DG used in our study is equivalent to the one shown to be safe in human clinical trials (23,24).…”

“…3 and 6). Several reports have indicated that 2DG administrated orally was safe and well tolerated by patients (23), leading to the launch of several phase II and III clinical trials in cancer therapy. Our study suggests that such cotreatment might be efficient not only by increasing the cytotoxicity of the chemotherapy but also by allowing the immune system to react against the tumor.…”

Organ-Specific Cancer Metabolism and Its Potential for Therapy

“…Additionally, high grade (Gleason > 7) and castration-resistant tumors seem to reactivate glycolysis, since FDG-PET and FDG-PET/CT studies indicate an increased glucose uptake compared to benign and low stage prostate cancers [153][154][155][156][157]. Accordingly, prostate cancer is affected by 2-deoxyglucose [158][159][160]. This is further in agreement with cell line studies, which show that the metastastic androgen-sensitive cell line LNCaP and the castration-resistant low-differentiation cell lines DU-145 and PC-3 are sensitive to glucose starvation [152] and that androgen signaling enhances the expression of glycolytic enzymes [161][162][163].…”

Switch of glycolysis to gluconeogenesis by dexamethasone for treatment of hepatocarcinoma

“…These enzymes in gluconeogenesis, namely phosphoenolpyruvate carboxykinase (PEPCK), fructose-1,6-bisphosphatase and glucose-6-phosphatase (G6Pase), convert oxaloacetate to phosphoenolpyruvate, fructose 1,6-bisphosphate to fructose 6-phosphate and glucose-6-phosphate to glucose, respectively, leading to an effective reversal of glycolysis [4][5][6] . Recently, metabolism of glucose by cancer cells has been intensively studied and targeting tumour metabolism is highlighted as a potential strategy against cancer [7][8][9][10] . However, how and whether gluconeogenesis affects tumour metabolism remains unclear.…”