Tumor treatment using continuous low dose applications of sugar analogs
Theodore Lampidis and Metin Kurtoglu
Problem
Cancer cells growing in the hypoxic regions of tumor cells produce energy by glycolytic utilization of glucose and thereby, inhibition of this metabolic pathway by 2-deoxy-D-glucose (2-DG) elicits cytotoxicity in portions of solid tumors that are devoid of adequate oxygenation (hypoxia). Furthermore, the 6 carbon skeleton of glucose molecule is used by tumor cells for forming the sugar backbones of DNA and RNA precursors as well as oligosachharides that are essential for synthesis of glycoproteins. Thus, enhanced glucose consumption is essential for maintaining the high demand of nucleic acid and glycoprotein synthesis in rapidly proliferating tumor cells which underlies the growth inhibitory effect of 2-DG in cancer cells undergoing rapid cell cycle in the presence of sufficient oxygen supply. Taken together, it suggests that 2-DG can be used as a single chemotherapeutic agent as a result of its combined effects on both normoxic and hypoxic regions of solid tumors.
Solution
The invention establishes a rate and dose of 2-DG administered by an infusion pump or by another continuous slow release delivery method. The rate and dose is selected to maintain a certain plasma concentration of 2-DG.
Competitive Advantage
The invention is a non-toxic treatment for cancer as well as other diseases.
Applications
The invention is a non-toxic treatment for cancer as well as other diseases.
Patent Status
International patent application No. PCT/US2009/045157 entitled TREATMENT USING CONTINUOUS LOW DOSE APPLICATION OF SUGAR ANALOGS was filed on May 26, 2009.
Licensing Opportunity
We are looking for a commercialization partner with capabilities in product development, sales, and marketing. An exclusive worldwide license is available.
About the Inventors
Dr. Theodore J. Lampidis' primary work has been focused on the molecular and cellular mechanisms responsible for Multi-drug Resistance (the process and phenomenon by which tumors initially respond to chemotherapy but eventually become resistant to that therapy and to subsequent therapies). Dr. Lampidis has contributed many papers addressing this serious clinical obstacle in cancer treatment. He has been regularly awarded grants from the National Institutes of Health in the division of the National Cancer Institute, and has been an invited Speaker at Memorial Sloan Kettering Cancer Institute (New York), Oxford University (Oxford England), Max Planck Institute (Munich Germany), MD Anderson Cancer Center (Houston Texas), Harvard Medical School, (Boston) and numerous other prestigious Institutes. He has acted as a consultant for a number of drug companies, including Bristol Myers Squibb, Wyeth Ayerst, Guilford Pharmaceuticals, and most recently Threshold Pharmaceuticals. He received two consecutive five year awards beginning in 2001 from the National Cancer Institute on his latest work which involves a strategy for selectively killing the slow growing cells found in the inner core of solid tumors using non-toxic analogs of glucose. If successful, his discoveries may increase the efficacy of many chemotherapeutic clinical protocols. The National Cancer Institute has stated that "Dr. Lampidis' work could eventually lead to cures in certain cancers."
Metin Kurtoglu is a young scientist who holds both an MD and Ph. D. degree. He has focused his studies on how the effects of glucose analogs such as 2-deoxyglucose leads to cell death in certain tumor cell types even when grown in the presence of oxygen by inducing endoplasmic reticulum stress. He along with his mentor, Dr. Lampidis, have been involved with investigating how to exploit fundamental differences in glucose metabolism between normal and tumor cells for therapeutic gain using sugar analogs. They have found that subtle chemical differences in these analogs have profound effects on glucose flux within the cell which contribute to meaningful biologic activity that can be used to selectively kill a variety of different tumor cell types.
Selected References
Wangpaichitr M, Savaraj N, Maher J, Kurtoglu M, Lampidis TJ. Intrinsically lower AKT, mammalian target of rapamycin, and hypoxia-inducible factor activity correlates with increased sensitivity to 2-deoxy-D-glucose under hypoxia in lung cancer cell lines. Mol Cancer Ther. 2008 Jun;7(6):1506-13.
Subbarayan PR, Wang PG, Lampidis TJ, Ardalan B, Braunschweiger P. Differential expression of Glut 1 mRNA and protein levels correlates with increased sensitivity to the glyco-conjugated nitric oxide donor (2-glu-SNAP) in different tumor cell types. J Chemother. 2008 Feb;20(1):106-11.
Boutrid H, Jockovich ME, Murray TG, Pi�a Y, Feuer WJ, Lampidis TJ, Cebulla CM.
Targeting hypoxia, a novel treatment for advanced retinoblastoma. Invest Ophthalmol Vis Sci. 2008 Jul;49(7):2799-805. Epub 2008 Mar 7.
Kurtoglu M, Gao N, Shang J, Maher JC, Lehrman MA, Wangpaichitr M, Savaraj N, Lane AN, Lampidis TJ. Under normoxia, 2-deoxy-D-glucose elicits cell death in select tumor types not by inhibition of glycolysis but by interfering with N-linked glycosylation.
Mol Cancer Ther. 2007 Nov;6(11):3049-58.
Kurtoglu M, Maher JC, Lampidis TJ. Differential toxic mechanisms of 2-deoxy-D-glucose versus 2-fluorodeoxy-D-glucose in hypoxic and normoxic tumor cells. Antioxid Redox Signal. 2007 Sep;9(9):1383-90. Review.
Maher JC, Wangpaichitr M, Savaraj N, Kurtoglu M, Lampidis TJ. Hypoxia-inducible factor-1 confers resistance to the glycolytic inhibitor 2-deoxy-D-glucose.
Mol Cancer Ther. 2007 Feb;6(2):732-41.
Lampidis TJ, Kurtoglu M, Maher JC, Liu H, Krishan A, Sheft V, Szymanski S, Fokt I, Rudnicki WR, Ginalski K, Lesyng B, Priebe W. Efficacy of 2-halogen substituted D-glucose analogs in blocking glycolysis and killing "hypoxic tumor cells". Cancer Chemother Pharmacol. 2006 Dec;58(6):725-34. Epub 2006 Mar 23.
Maher JC, Savaraj N, Priebe W, Liu H, Lampidis TJ. Differential sensitivity to 2-deoxy-D-glucose between two pancreatic cell lines correlates with GLUT-1 expression. Pancreas. 2005 Mar;30(2):e34-9.
Maschek G, Savaraj N, Priebe W, Braunschweiger P, Hamilton K, Tidmarsh GF, De Young LR, Lampidis TJ. 2-deoxy-D-glucose increases the efficacy of adriamycin and paclitaxel in human osteosarcoma and non-small cell lung cancers in vivo. Cancer Res. 2004 Jan 1;64(1):31-4.
Maher JC, Krishan A, Lampidis TJ. Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-D-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemother Pharmacol. 2004 Feb;53(2):116-22. Epub 2003 Nov 7.
Hu YP, Haq B, Carraway KL, Savaraj N, Lampidis TJ. Multidrug resistance correlates with overexpression of Muc4 but inversely with P-glycoprotein and multidrug resistance related protein in transfected human melanoma cells. Biochem Pharmacol. 2003 May 1;65(9):1419-25.
Liu H, Savaraj N, Priebe W, Lampidis TJ. Hypoxia increases tumor cell sensitivity to glycolytic inhibitors: a strategy for solid tumor therapy (Model C). Biochem Pharmacol. 2002 Dec 15;64(12):1745-51.
Liu H, Hu YP, Savaraj N, Priebe W, Lampidis TJ. Hypersensitization of tumor cells to glycolytic inhibitors. Biochemistry. 2001 May 8;40(18):5542-7.
Hu Y, Moraes CT, Savaraj N, Priebe W, Lampidis TJ. Rho(0) tumor cells: a model for studying whether mitochondria are targets for rhodamine 123, doxorubicin, and other drugs. Biochem Pharmacol. 2000 Dec 15;60(12):1897-905.
