News Release
 

May 8, 2012

CONTACT: Karen Kreeger
215-349-5658
Karen.kreeger@uphs.upenn

Perelman School of Medicine


This release is available online at
http://www.uphs.upenn.edu/news/News_Releases/2012/05/block/

Block Its Recycling System, and Cancer Kicks the Can, According to New Penn Study

Potent new drug kills tumor cells in mice by clogging up their recycling system

PHILADELPHIA — All cells have the ability to recycle unwanted or damaged proteins and reuse the building blocks as food. But cancer cells have ramped up the system, called autophagy, and rely on it to escape damage in the face of chemotherapy and other treatments. Now, researchers at the Perelman School of Medicine; the Abramson Cancer Center; and the School of Arts and Sciences, at the University of Pennsylvania, have developed a potent new drug that clogs up the recycling machinery and kills tumor cells in mouse models.

Ravi K. Amaravadi, MD, assistant professor of Medicine, and colleagues showed previously that an old malaria drug, hydroxychloroquine, reduces autophagy in cancer cells and makes them more likely to die when exposed to chemotherapy. The strategy is currently being tested in clinical trials, and preliminary results are promising. The catch, though, is that it's not always possible to give patients a high enough dose of hydroxychloroquine to have an effect on their tumor cells.

Amaravadi teamed up with Jeffrey Winkler, PhD, the Merriam Professor of Chemistry, to design a series of more potent versions of chloroquine. They describe the design, chemical synthesis, and biological evaluation of a highly effective, new compound called Lys05, in the early edition of the Proceedings of the National Academy of Sciences this week.

Unlike hydroxychloroquine, which has little impact on tumor cells when used as a single agent, the new drug, called Lys05, slows tumor growth in animal models even in the absence of other anti-tumor therapies. What's more, the Lys05 dose that is toxic to cancer cells, which are addicted to recycling and rely on it much more heavily than healthy cells, has little or no effect on healthy cells.

"We see that Lys05 has anti-tumor activity at doses that are non-toxic for the animals," Amaravadi says. "This single-agent anti-tumor activity suggests this drug, or its derivative, may be even more effective in patients than hydroxychloroquine." Remarkably, however, when the investigators increase the dose of Lys05, some animals develop symptoms that mimic a known genetic deficiency in an autophagy gene, ATG16L1, which affects some patients with Crohn's disease . That similarity — technically called a phenocopy — clearly shows that Lys05 works by interfering with the recycling system in cells.

Lys05, and its companion compound Lys01, aren't quite ready for testing in patients, according to Amaravadi. Before that can happen, the molecules need to be optimized and undergo more toxicity testing in animals. Amaravadi and Winkler hope to team up with an industry partner for that portion of the project.

In the meantime, though, Amaravadi says the work illustrates just how important autophagy is to cancer cells, and provides an important 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, John P. Lynch, Takeshi Uehara, and Antonia R. Sepulveda, all from Penn, and Lisa E. Davis from the University of the Sciences in Philadelphia.

The work was supported by an Abramson Cancer Center pilot award and the National Cancer Institute (1K23CA120862) and a seed grant from the Abramson Cancer Center.

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Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $4.3 billion enterprise.

The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 17 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $392 million awarded in the 2013 fiscal year.

The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania -- recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report; Penn Presbyterian Medical Center; Chester County Hospital; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine.

Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2013, Penn Medicine provided $814 million to benefit our community.