Blocking cancer's recycling system

According to a study published in the Proceedings of the National Academy of Sciences, researchers at the Perelman School of Medicine, the Abramson Cancer Center and the School or Arts and Sciences at the University of Pennsylvania have developed a new drug called Lys05 which blocks the process of recycling in cancer cells, thus preventing autophagy - which cancer cells rely on to escape damage from chemotherapy and other treatments. Furthermore, the team found that Lys05 kills tumor cells in mice. Ravi K. Amaravadi, M.D., assistant professor of Medicine, and colleagues previously demonstrated that hydroxychloroquine (an old malaria drug) is able to reduce autophahy in cancer cells and also enhance the effect of chemotherapy. The drug is currently being examined in human trials. Even though preliminary results are promising, the researchers note that it is not always possible to give patients a high enough dose of the drug to be effective on their tumor cells. In order to design a series of stronger versions of the drug, Amaravadi teamed up with Jeffrey Winkler, Ph.D., the Merriam Professor of Chemistry. In this study, they highlight the design, chemical synthesis and biological evaluation of Lys05. The researchers observed that unlike to hydroxzychloroquine, which has only a small effect on tumor cells when used as a single agent, Lys05 was able to reduce the growth of tumors in mice models even when other anti-tumor therapies were absent. Furthermore, the team found that although Lys05 is toxic to cancer cells, it has little or no effect on healthy cells. Amaravadi explained: "We see that Lys05 has anti-tumor activity at doses that are non-toxic for the animals. This single-agent anti-tumor activity suggests this drug, or its derivative, may be even more effective in patients than hydroxychloroquine." The researchers found that when the dose of Lys05 was increased, some mice developed symptoms that mirror a known genetic deficiency in an autophagy gene, ATG16L1, which affects some individuals with Crohn's disease. According to the researchers, this phenocopy (similarity) shows that the drug works by blocking the recycling system in cells. Before Lys05 and its companion compound Lys01 can be tested in patients, the molecules need to be optimized and be tested further in animal models. According to Amaravadi, the work demonstrates just how vital autophagy is to cancer cells, and also paves the way for future therapies. Study co-authors include Quentin McAfee, Zhihui Zhang, Arabinda Samanta, Samuel M. Levi, Xiao-Hong Ma, Shengfu Piao, John P. Lynch, Takeshi Uehara, and Antonia R. Sepulveda, all from Penn, and Lisa E. Davis from the University of the Sciences in Philadelphia.