(provided by PI): Cancer cells are metabolically different from normal matching cells, and this is manifested by the high rate of glucose metabolism in cancer cells. Because high rate of aerobic glycolysis distinguishes cancer cells from normal cells it is exploited for the selective imaging of cancer cells in vivo through the utilization of the glucose analog fluoro-2-deoxyglucose (FDG) in positron emission tomography (PET). PET is used following injection of [18F]-FDG, which is then being taken by glycolytic cancer cells and is phosphorylated by hexokinase to form FDG-6-phosphate, which can then be detected by PET. The phosphorylation of FDG retains and accumulates the labeled FDG inside cells because unlike phosphorylated glucose it cannot be further utilized in glycolysis. Thus, the success of the FDG-PET scan could be explained by the higher activity of hexokinase in cancer cells when compared to normal cells. This observation raises the question; if higher activity of hexokinase is exploited to selectively image cancer cell, why it cannot be exploited to selectively target the cancer cells. This could be challenging because hexokinase, which catalyzes the first committed step in glucose metabolism is critical for every living cell. However, there are several hexokinase isoforms. Most normal adult tissues and cells express hexokinase 1 (HK1), but when they convert into cancer cells they start expressing high levels of hexokinase 2 (HK2). Thus, the high expression of HK2 distinguishes cancer cells from normal cells, and determines the success of FDG-PET scan. To assess the requirement of HK2 for cancer development and whether its ablation could selectively target the cancer cells, in the current funding period, we have generated mice in which we could systemically delete HK2 before or after tumor onset. By employing this mouse model we provided a genetic proof of concept that systemic HK2 inhibition is well-tolerated and therapeutic for lung and breast cancer. In this grant proposal we will further explore new observations and consequences of HK2 ablation in and breast and prostate cancer progression and metastasis both at the organismal and cellular levels.
Studies suggest that veterans are at a higher risk of developing prostate and breast cancer than the rest of the population. We found that in human prostate carcinoma and in breast cancer hexokinase 2 (HK2) expression is markedly elevated, while in normal prostate and mammary gland cells its expression is not detectable. HK2 catalyzes the first committed step in glucose metabolism, and is critical for the high glucose metabolism in cancer cells, which distinguishes them from normal cell. Our long-term goal is to develop strategies that exploit the accelerated glucose metabolism in cancer cells to selectively eradicate them. We provided a genetic proof of concept that systemic HK2 inhibition is well-tolerated and therapeutic for cancer in mouse models for lung and breast cancer. Likewise ablation of HK2 expression in human cancer cells inhibited the growth of the tumors after tumor formation. In this grant proposal we will further explore new observations and consequences of HK2 ablation in and breast and prostate cancer progression and metastasis both at the organismal and cellular levels
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