Ravi K. Amaravadi, MD, assistant professor of Medicine, andcolleagues showed previously that an old malaria drug,hydroxychloroquine, reduces autophagy in cancer cells and makesthem more likely to die when exposed to chemotherapy. The strategyis currently being tested in clinical trials, and preliminaryresults are promising. The catch, though, is that it's not alwayspossible to give patients a high enough dose of hydroxychloroquineto have an effect on their tumor cells. Amaravadi teamed up with Jeffrey Winkler, PhD, the MerriamProfessor of Chemistry, to design a series of more potent versionsof chloroquine. |
They describe the design, chemical synthesis, andbiological evaluation of a highly effective, new compound calledLys05, in the early edition of the Proceedings of the National Academy of Sciences this week. Unlike hydroxychloroquine, which has little impact on tumor cellswhen used as a single agent, the new drug, called Lys05, slowstumor growth in animal models even in the absence of otheranti-tumor therapies. What's more, the Lys05 dose that is toxic tocancer cells, which are addicted to recycling and rely on it muchmore heavily than healthy cells, has little or no effect on healthycells. "We see that Lys05 has anti-tumor activity at doses that arenon-toxic for the animals," Amaravadi says.
"Thissingle-agent anti-tumor activity suggests this drug, or itsderivative, may be even more effective in patients thanhydroxychloroquine." Remarkably, however, when theinvestigators increase the dose of Lys05, some animals developsymptoms that mimic a known genetic deficiency in an autophagygene, ATG16L1, which affects some patients with Crohn's disease .That similarity -- technically called a phenocopy -- clearly showsthat Lys05 works by interfering with the recycling system in cells. Lys05, and its companion compound Lys01, aren't quite ready fortesting in patients, according to Amaravadi. Before that canhappen, the molecules need to be optimized and undergo moretoxicity testing in animals. Amaravadi and Winkler hope to team upwith an industry partner for that portion of the project.
In the meantime, though, Amaravadi says the work illustrates justhow important autophagy is to cancer cells, and provides animportant new step for future therapies. Co-authors on the paper include Quentin McAfee, Zhihui Zhang,Arabinda Samanta, Samuel M. Levi, Xiao-Hong Ma, Shengfu Piao, JohnP. Lynch, Takeshi Uehara, and Antonia R.
Sepulveda, all from Penn,and Lisa E. Davis from the University of the Sciences inPhiladelphia. The work was supported by an Abramson Cancer Center pilot award andthe National Cancer Institute (1K23CA120862) and a seed grant fromthe Abramson Cancer Center.
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