Faculty : Departmental- Primary

Theodore J. Lampidis, Ph.D.

The current research interests of our laboratory derive from our 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). Our 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 our studies on mitochondrial agents we 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, these tumor cells by the nature of their slow growth exhibit a form of MDR, which contributes significantly to chemotherapy failures in the treatment of solid tumors. Anaerobiosis, however, provides a natural window of selectivity for agents that interfere with glycolysis, which is now one of the central theme of our research efforts.

As illustrated in Figure 1 two windows of selectivity exist that can be exploited with inhibitors of glycolysis (2-deoxyglucose (2-DG)) to selectively kill the hypoxic slow growing population of cells found in most solid tumors while sparing the normal aerobic cells: (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 normal aerobic cells to block glycolysis, by the nature of their mitochondria having access to oxygen they can survive by burning other fuels for energy such as fats and proteins.

undefined

Fig 1. Schematic illustration demonstrating different consequences of blocking glycolysis in aerobic vs hypoxic cells. In the aerobic normal cell if glycolysis is inhibited by 2-DG ATP cannot be generated by this pathway. However, since O 2 is available to the mitochondria, amino acids and or fatty acids can act as alternative energy sources for oxidative phosphorylation to take place producing ATP. In contrast, when glycolysis is blocked in the hypoxic tumor cell, other carbon sources cannot be used by mitochondria since O 2 is unavailable and consequently oxidative phosphorylation cannot take place. Thus, when glycolysis is blocked by 2-DG in the hypoxic cell, it has no alternative means for generating ATP and will therefore succumb to this treatment.

Three distinct tumor cell models of simulated hypoxia or anaerobiosis have been developed in our laboratory to examine this natural phenomenon and all show increased lactic acid production ( a measure of glycolysis) and hypersensitivity to glycolytic inhibitors. Model A (Chemical model of “hypoxia”) represents tumor cells treated at a dose of rhodamine 123 which specifically uncouples ATP synthesis from electron transport; Model B (genetic model of “hypoxia”) are Rho 0 cells which have lost their mitochondrial DNA and therefore cannot undergo oxidative phosphorylation, and Model C (environmental model of hypoxia) denotes tumor cells which are growing under reduced levels of oxygen (5 to 0.1 %). We have demonstrated that the glycolytic inhibitor 2-deoxy-D-glucose (2-DG) raises the efficacy of standard chemotherapeutic agents (which target the rapidly growing aerobic tumor cells) by presumably targeting the slow-growing population of solid tumors.

By use of these 3 distinct models of anerobiosis we have recently found and 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 have laid the groundwork for subsequent preliminary work in which we find that mTOR inhibitors can be used to increase the sensitivity to 2-DG by down-regulating HIF-1.

Based on our in vitro and in vivo data and with the efforts of Dr. George Tidmarsh of Threshold Pharmaceuticals, Drs. Joseph Rosenblatt and Luis Raez in Miami, a Phase I clinical trial has been initiated in Feb 2004 at the Sylvester Comprehensive Cancer Center in Miami and at the San Antonio Cancer Center in Texas: Protocol #2003121, “ A Phase I dose escalation trial of 2-deoxy-D-glucose alone and in combination with docetaxel in subjects with advanced solid malignancies”. To date (May 2007), 2-DG appears to be non-toxic in 32 patients treated with this protocol.

With our Phase I clinical trial now in progress we are closer to achieving our long-term goal of using glycolytic inhibitors, in conjunction with standard cancer chemotherapy, to enhance its efficacy by selectively killing the anaerobic, slow-growing tumor cells found at the inner core of solid tumors which are usually the most resistant and consequently the most difficult to eradicate.

Recently we have discovered that a percentage of tumor cells under normoxic conditions are killed with 2-DG but not other glycolytic inhibitors. We have uncovered a mechanism of interference with N-linked glycosyaltion that appears to be responsible for this effect. Studies are ongoing to determine the mechanism by which these types of tumor cells are selectively sensitive to the toxic effects of 2-DG under normoxic conditions while most other tumor or normal cells are not. Our long-term goal is to be able to exploit these findings for the eventual clinical use of 2-DG as a single agent with dual activity in interfering with glycosylation in the aerobic portion as well as inhibiting glycolysis in the hypoxic portion of these types of solid tumors thereby killing both malignant cell populations with this relatively non-toxic treatment.

Professional Affiliations

University of Miami Sylvester Comprehensive Cancer Center

Select Publications

  • 2013 Luis E. Raez; Kyriakos Papadopoulos; Alejandro D. Ricart; E. Gabriella Chiorean; Robert S. Dipaola; Mark N. Stein; Caio M. Rocha Lima; James J. Schlesselman; Khaled Tolba; Virginia K. Langmuir; et al.
    A phase i dose-escalation trial of 2-deoxy-d-glucose alone or combined with docetaxel in patients with advanced solid tumors
    Cancer Chemotherapy and Pharmacology. 2013;71(2):523-530. 2
  • 2013 Samuel K. Houston; Theodore J. Lampidis; Timothy G. Murray
    Models and discovery strategies for new therapies of retinoblastoma
    Expert Opinion on Drug Discovery. 2013;8(4):383-394. 0
  • 2013 Haibin Xi; Julio C. Barredo; Jaime R. Merchan; Theodore J. Lampidis
    Endoplasmic reticulum stress induced by 2-deoxyglucose but not glucose starvation activates AMPK through CaMKKβ leading to autophagy
    Biochemical Pharmacology. 2013;85(10):1463-1477. 2
  • 2013 Huaping Liu; Metin Kurtoglu; Yenong Cao; Haibin Xi; Rakesh Kumar; Jeffrey M. Axten; Theodore J. Lampidis
    Conversion of 2-deoxyglucose-induced growth inhibition to cell death in normoxic tumor cells
    Cancer Chemotherapy and Pharmacology. 2013;72(1):251-262. 0
  • 2012 Medhi Wangpaichitr; Elizabeth J. Sullivan; George Theodoropoulos; Chunjing Wu; Min You; Lynn G. Feun; Theodore J. Lampidis; Macus T. Kuo; Niramol Savaraj
    The relationship of thioredoxin-1 and cisplatin resistance: Its impact on ROS and oxidative metabolism in lung cancer cells
    Molecular Cancer Therapeutics. 2012;11(3):604-615. 1
  • 2012 Yolanda Piña; Christina Decatur; Timothy G. Murray; Samuel K. Houston; Milena Lopez-Cavalcante; Eleut Hernandez; Magda Celdran; Nikesh Shah; William Feuer; Theodore Lampidis
    Retinoblastoma treatment: Utilization of the glycolytic inhibitor, 2-deoxy-2-fluoro-d-glucose (2-FG), to target the chemoresistant hypoxic regions in LH BETAT AG retinal tumors
    Investigative Ophthalmology and Visual Science. 2012;53(2):996-1002. 0
  • 2012 Yolanda Piña; Samuel K. Houston; Timothy G. Murray; Tulay Koru-Sengul; Christina Decatur; William K. Scott; Lubov Nathanson; Jennifer Clarke; Theodore J. Lampidis
    Retinoblastoma treatment: Impact of the glycolytic inhibitor 2-deoxy-d-glucose on molecular genomics expression in LH BETAT AG retinal tumors
    Clinical Ophthalmology. 2012;6(1):817-830. 0
  • 2012 Joanna DeSalvo; Jeffim N. Kuznetsov; Jianfeng Du; Gilles M. Leclerc; Guy J. Leclerc; Theodore J. Lampidis; Julio C. Barredo
    Inhibition of Akt potentiates 2-DG – Induced apoptosis via downregulation of UPR in acute lymphoblastic leukemia
    Molecular Cancer Research. 2012;10(7):969-978. 1
  • 2012 Howard J. Leung; Elda M. Duran; Metin Kurtoglu; Samita Andreansky; Theodore J. Lampidis; Enrique A. Mesri
    Activation of the unfolded protein response by 2-deoxy-D-Glucose Inhibits Kaposi’s sarcoma-associated herpesvirus replication and gene expression
    Antimicrobial Agents and Chemotherapy. 2012;56(11):5794-5803. 1
  • 2011 Samuel K. Houston; Yolanda Piña; Timothy G. Murray; Hinda Boutrid; Colleen Cebulla; Amy C. Schefler; Wei Shi; Magda Celdran; William Feuer; Jaime Merchan; et al.
    Novel retinoblastoma treatment avoids chemotherapy: The effect of optimally timed combination therapy with angiogenic and glycolytic inhibitors on LH BETAT AG retinoblastoma tumors
    Clinical Ophthalmology. 2011;5(1):129-137.

View published research articles by Dr. Lampidis in the National Library of Medicine.