Theodore Lampidis, Ph.D.
Professor of Cell Biology & Anatomy
Description of Research
The current research interests of Dr. Lampidis' laboratory derive from his long-term studies on understanding the mechanisms of tumor cell resistance and the structure/function requirements of various chemotherapeutic agents for recognition by p-glycoprotein (P-gp)-mediated multiple drug resistance (MDR). His work has shown that the mitochondrial agent rhodamine 123 is a substrate for this P-gp drug effluxing pump. Hence it is commonly used to detect this form of MDR in freshly isolated human tumor biopsies for determining which protocols patients may best benefit from.
As an outcome of their studies on mitochondrial agents, Dr. Lampidis and his colleagues realized that tumor cells treated with the uncoupling agent, rhodamine 123, were strikingly similar to the poorly oxygenated (hypoxic) cancer cells located at the inner core of solid tumors. The similarity is that in both conditions the cells rely exclusively on anaerobic metabolism for survival. Moreover, cells in the center of a tumor divide more slowly than outer growing aerobic cells and consequently are more resistant to standard chemotherapeutic agents which target the more rapidly dividing cells. Thus, by the nature of their slow growth, the hypoxic tumor cell population found within most solid tumors are resistant to most standard chemotherapeutic drugs which target rapidly cycling cells. Therefore, slow growth represents another form of MDR, which contributes significantly to chemotherapy failures in the treatment of solid tumors. However, hypoxia provides a natural window of selectivity for agents that interfere with glycolysis by forcing tumor cells in this microenvironment to rely mainly on glycolysis for survival. This forms one of the major themes of Dr. Lampidis' lab: Use of inhibitors of glycolysis (2-deoxyglucose (2-DG)) to selectively kill the hypoxic slow growing population of cells while sparing most normal cells that comprise the majority of tissues which are slow growing but under normal oxygen conditions. Thus, the two natural windows that can be exploited are (1) hypoxic tumor cells accumulate more 2-DG than normal aerobic cells, and (2) when glycolysis is blocked in hypoxic cells, their remaining source of ATP is stopped and therefore they succumb to this treatment. In contrast, even if enough 2-DG accumulates in our normal aerobic cells to block glycolysis, as long as their mitochondria have access to oxygen, they can survive by burning other fuels for energy such as fats and proteins.
Using three distinct tumor cell models of simulated hypoxia or anaerobiosis developed in the laboratory, all show increased lactic acid production (a measure of glycolysis) and hypersensitivity to glycolytic inhibitors. Dr. Lampidis and his colleagues reported that hypoxic inducible factor-1 (HIF-1) confers a level of resistance to glycolytic inhibitors that can be overcome by siRNA specific to HIF-1. These studies laid the groundwork for subsequent work in which they found that mTOR inhibitors can be used to increase the sensitivity to 2-DG by down-regulating HIF-1.
The translation of Dr. Lampidis' in vitro and in vivo results in the clinic are the following:
- Bench to clinic to bench back to clinic: After completion of their Phase I clinical trial Dr. Lampidis' team learned that oral once per day drink can induce an insulin response to 2-DG as well as liver adsorption which will decrease the amount of this sugar getting to the tumor. Therefore, before they progress to a Phase II clinical trial, they will further investigate and develop the most efficient drug delivery, i.e. slow release pump, pill or diet.
- Phase I Pilot Trial in Children with Retinoblastoma: In collaboration with Dr. Tim Murray, a leading expert in the investigation and treatment of children with retinoblastoma at the Bascom Palmer Eye Institute, Dr. Lampidis and his colleagues have demonstrated that the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) raises the efficacy of the chemotherapeutic agent (carboplatin). used to treat this disease Moreover using piminidazole, which identifies hypoxic tumor cells, they have provided the first proof of principle that indeed 2-DG, but not carbopaltin, targets and kills the hypoxic portion of this tumor. Based on these very encouraging in vivo results, they plan to begin a pilot Phase I trial in patients whose eyes cannot be saved by current treatments.
- Multiple Myeloma Phase I/II study: Dr. Kurtoglu, a scientist in Dr. Lampidis' lab, found that a drug used in millions of people to lower cholesterol has selective toxic effects on multiple myeloma cancer cells. They plan to start this trial soon.
Selected Cancer-Related Publications
- Raez LE, Papadopoulos K, Ricart AD, Chiorean EG, Dipaola RS, Stein MN, Rocha Lima CM, Schlesselman JJ, Tolba K, Langmuir VK, Kroll S, Jung DT, Kurtoglu M, Rosenblatt J, Lampidis TJ. A phase I dose-escalation trial of 2-deoxy-D-glucose alone or combined with docetaxel in patients with advanced solid tumors. Cancer Chemother Pharmacol 71:523-30,2013 Read more »
- Houston SK, Lampidis TJ, Murray TG. Models and discovery strategies for new therapies of retinoblastoma. Expert Opin Drug Discov 8:383-94,2013 Read more »
- Liu H, Kurtoglu M, Cao Y, Xi H, Kumar R, Axten JM, Lampidis TJ. Conversion of 2-deoxyglucose-induced growth inhibition to cell death in normoxic tumor cells. Cancer Chemother Pharmacol 72:251-62,2013 Read more »
- Piña Y, Houston SK, Murray TG, Koru-Sengul T, Decatur C, Scott WK, Nathanson L, Clarke J, Lampidis TJ. Retinoblastoma treatment: impact of the glycolytic inhibitor 2-deoxy-d-glucose on molecular genomics expression in LH(BETA)T(AG) retinal tumors. Clin Ophthalmol 6:817-30,2012 Read more »
- Leung HJ, Duran EM, Kurtoglu M, Andreansky S, Lampidis TJ, Mesri EA. Activation of the Unfolded Protein Response by 2-Deoxy-D-Glucose Inhibits Kaposi's Sarcoma-Associated Herpesvirus Replication and Gene Expression. Antimicrob Agents Chemother :,2012 Read more »
- Piña Y, Decatur C, Murray TG, Houston SK, Lopez-Cavalcante M, Hernandez E, Celdran M, Shah N, Feuer W, Lampidis T. Retinoblastoma Treatment: Utilization of the Glycolytic Inhibitor,2-deoxy-2-fluoro-D-glucose (2-FG),to Target the Chemoresistant Hypoxic Regions in LHBETATAG Retinal Tumors. Invest Ophthalmol Vis Sci 53:996-1002,2012 Read more »
- Desalvo J, Kuznetsov JN, Du J, Leclerc GM, Leclerc GJ, Lampidis TJ, Barredo JC. Inhibition of Akt Potentiates 2-DG-Induced Apoptosis via Downregulation of UPR in Acute Lymphoblastic Leukemia. Mol Cancer Res 10:969-78,2012 Read more »
- Wangpaichitr M, Sullivan EJ, Theodoropoulos G, Wu C, You M, Feun LG, Lampidis TJ, Kuo MT, Savaraj N. The Relationship of Thioredoxin-1 and Cisplatin Resistance: Its Impact on ROS and Oxidative Metabolism in Lung Cancer Cells. Mol Cancer Ther 11:604-15,2012 Read more »
- Xi H, Kurtoglu M, Liu H, Wangpaichitr M, You M, Liu X, Savaraj N, Lampidis TJ. 2-Deoxy-D: -glucose activates autophagy via endoplasmic reticulum stress rather than ATP depletion. Cancer Chemother Pharmacol 67:899-910,2011 Read more »
- Piña Y, Decatur C, Murray T, Houston S, Gologorsky D, Cavalcante M, Cavalcante L, Hernandez E, Celdran M, Feuer W, Lampidis T. Advanced retinoblastoma treatment: targeting hypoxia by inhibition of the mammalian target of rapamycin (mTOR) in LH(BETA)T(AG) retinal tumors. Clin Ophthalmol 5:337-43,2011 Read more »
- Houston SK, Piña Y, Murray TG, Boutrid H, Cebulla C, Schefler AC, Shi W, Celdran M, Feuer W, Merchan J, Lampidis TJ. Novel retinoblastoma treatment avoids chemotherapy: the effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LH(BETA)T(AG) retinoblastoma tumors. Clin Ophthalmol 5:129-37,2011 Read more »
- Merchan JR, Kovács K, Railsback JW, Kurtoglu M, Jing Y, Piña Y, Gao N, Murray TG, Lehrman MA, Lampidis TJ. Antiangiogenic activity of 2-deoxy-d-glucose. PLoS One 5:e13699,2010 Read more »
- Piña Y, Houston SK, Murray TG, Boutrid H, Celdran M, Feuer W, Shi W, Hernandez E, Lampidis TJ. Focal,Periocular Delivery of 2-Deoxy-D-Glucose as Adjuvant to Chemotherapy for Treatment of Advanced Retinoblastoma. Invest Ophthalmol Vis Sci 51:6149-6156,2010 Read more »
Collaborating in the Multidisciplinary Research Program(s):