Peng Huang, M.D., Ph.D.
University of Texas M. D. Anderson Cancer Center
Abstract:
Significant progresses made in recent year in our understanding of the biology and clinical treatment of chronic lymphocytic leukemia (CLL). However, many challenges still remain. Development of drug resistance to current anti-CLL drugs Remains a significant problem in the treatment of disease. Thus, identification and development of new compounds that preferentially kill CLL cells with relative low toxic effect on normal cells are important research tasks. Our recent studies showed that CLL cells exhibit certain abnormalities including high frequency of mutations in mitochondrial DNA, aberrant mitochondrial biogenesis, and increased generation of reactive oxygen species (ROS).
These abnormalities appear to be associated with less sensitivity to fludarabine, a drug of choice from frontline treatment of CLL. Based on our study and understanding of energy metabolism in cancer cells, we speculate that such molecular and biochemical alterations in CLL cells may be exploited for therapeutic benefits, and new drugs can be designed to preferentially target these abnormalities. We hypothesize that malfunction of mitochondria (the cellular organelle that normally produce ATP as the energy source for the cells) may render CLL cells highly dependent on the alternative ATP generation pathway known as glycolysis, and that inhibition of this alternative pathway would cause a severe depletion of ATP in CLL cells, leading to the death of these cancer cells. On the other hand, normal cell may be able to better tolerate glycolytic inhibition due to normal mitochondrial functions.
Our laboratory has synthesized a novel compound named glycolycin that effectively inhibits glycolysis. Preliminary studies showed that this compound effectively depletes cellular ATP and kills CLL cells in vitro. Importantly, glycolycin remains active in CLL cells that became resistant to fludarabine. In this research project, we propose to evaluate the in vitro anti-CLL activity of glycolycin and validate the drug target in CLL cells, to test the in vivo therapeutic activity of glycolycin in CLL animal model, and to conduct animal toxicology study to determine the toxicity/safety profiles of this compound. We anticipate that this research project will generate important data leading to the development of a novel anticancer agent for the treatment of CLL and other cancer, and provide important information necessary for the design of future clinical trials.