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.
Highlights
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
- Kurtoglu M, Lampidis TJ. From delocalized lipophilic cations to hypoxia: blocking tumor cell mitochondrial function leads to therapeutic gain with glycolytic inhibitors. Mol Nutr Food Res 53:68-75, 2009. Read more »
Programs
Collaborating in the Multidisciplinary Research Program(s):