to a Cancer Cure
words by Maryann Brinley / photograph by John Emerson
ne day in 1980, Leroy Liu’s distinguished neighbor at Johns Hopkins School of Medicine dropped by to greet him and ask what he was doing. “Our labs were adjacent,” recalls Liu, who was a new professor there at the time. Paul Talalay, MD, was chair of the Department of Pharmacology and Liu told him, “I am working on something fantastic that can change the tertiary structure of DNA.”
A chemist at heart, Liu had landed his job at Johns Hopkins as a result of ground-breaking work begun during his PhD years at the University of California at Berkeley and subsequently during his postdoctoral years at Harvard University and University of California at San Francisco. Liu discovered type II DNA topoisomerases and was actually involved in naming the topoisomerases, a class of enzymes that can change the topology of DNA. This class of enzymes
performs “topological transformation. It’s very beautiful and really like playing magic.
Often, DNA, like strands of spaghetti, are entangled, which requires topoisomerases for disentangling during cell division and gene expression. The enzymes disentangle the chromosomal DNA by a cut-and-paste mechanism, like untying a knot or separating two interlocked circles.”
Liu expected Talalay to say something complimentary. Instead, Talalay replied, “Maybe your work will be relevant to medicine one day.” The researcher remembers thinking, “Are you saying it’s not relevant today?”
“Of course, this was my interpretation of his reaction,” he admits, but because of Talalay’s comment, Liu started looking for a closer connection between topoisomerase and medical applications.
“Some powerful anti-cancer drugs such as doxorubicin break down chromosomal DNA of cancer cells in a strikingly reversible manner but nobody knew what was really going on in the early ’³780s,” Liu recalls. Motivated by Talalay’s comment, he quickly realized that these anti-cancer drugs might act on human DNA topoisomerase II. Liu and his team, in a series of experiments, demonstrated that these anti-cancer agents subvert the normal cut-and-paste action of human DNA topoisomerase II and convert the enzyme into a DNA breaking machine. “In the presence of these anti-cancer agents, topoisomerase II can cut but not paste the chromosomal DNA, resulting in the formation of a unique topoisomerase II-drug-DNA ternary complex,” which he named the cleavable complex. “The replication fork actually collides with this complex leading to tumor cell death.”
Liu reaches for a loop of red plastic, a twist of coil created to bring the chemistry and DNA he loves so much to light. “See how this breaks apart,” he asks, unknotting the coil to make a double-strand cut and then rejoining it. “Simply speaking, these anti-cancer drugs allow topoisomerase II to proceed in its cutting action on DNA but prevent the pasting action. The net result is breakdown of the chromosomal DNA.”
Unfortunately, creating cancer-fighting drugs is a never-ending journey, according to Liu. “Unlike infectious diseases, where pathogens in a body can be lowered by one antibiotic to a point at which the immune system will take over the fight, cancer cells are insensitive to the immune system. Consequently, in order to cure cancer, every single cancer cell has to be killed by the anti-cancer agents. No single agent can kill all cancer cells due to the large number of them and the various drug-resistance mechanisms,” Liu explains. “So, the strategy for killing every cancer cell and fighting drug resistance is to develop new agents with different mechanisms of action and to find new molecular targets.”
Since his arrival at RWJMS in 1992, Liu has teamed up with Edmond Lavoie, PhD, in the Department of Medicinal Chemistry at Rutgers. “We work out the mechanisms. He makes the compounds.” One drug that he points to with pride was isolated from a plant alkaloid, camptothecin, found in the Camptothecin acuminata tree, native to Southern China, known as the happy tree, and with a history of anti-cancer activity in Chinese medical texts that can be traced back 2,000 years. “I looked at all that early Chinese literature. Not only did the compound have cancer-fighting properties for solid tumors, but it was also used for ringworm infection and other purposes. The fruit has the highest anti-cancer power.
“All trees make chemicals to fight off invaders. I was the first person to show the mechanism of action for camptothecins, which target DNA topoisomerase I rather than II. In the presence of camptothecins, a topoisomerase I-camptothecin-DNA ternary complex is formed. The collision between this complex and the replication fork leads to tumor cell death.”
Several camptothecins moved into clinical use in the 1990s. “Those were the glory days,” Liu recalls. Unfortunately, the drug was chemically unstable. So Liu and his team at RWJMS/Rutgers spent years developing a new class of topoisomerase I-targeting drugs, based on the isoquinoline alkaloid (berberine) isolated from a Chinese herb. The new compound, Genz-644282, is his most recently patented product and was licensed to Genzyme. It is now in multi-site Phase I clinical trials, which began in July 2009. The Cancer Institute of New Jersey (CINJ) is slated to become one of the sites testing this compound in patients with solid tumors.
“Everything is going well so far.” But it’s early, he cautions. For information, go to ClinicalTrials.gov and use the identifier, NCT00942799, for this study.
“All my life, I’ve worked on DNA, one-strand, two-strand, three-strand, four-strand…but the topology, or structure of it, not its sequence. The more we know, the more we can see that topology plays an important role in controlling cell division and gene expression.” And in the lab, Liu has moved on to other exciting projects, including four-stranded DNA. Liu found that four-stranded DNA exhibit strong anti-tumor activity. In collaboration with LaVoie, Joseph Rice, PhD, Rutgers, and Daniel Pilch, PhD, RWJMS, Liu identified this novel class of compounds, known as the G-quadruplex stabilizers. “These four-stranded DNA/RNA agents are still in early stage development as anti-cancer agents but we are hopeful that they can be developed into clinical use in the future.”
Over the years, Liu has been recognized by the international cancer community. The Sloan-Kettering Institute for Cancer Research chose him for its C. Chester Stock Award given to just one person annually who has advanced understanding of cancer. He also won the Bruce F. Cain Award for Outstanding Preclinical Research in Cancer Chemotherapy, the George H. Hitchings Award for Innovative Drug Design, the Searle Scholar Award and the Academician from the Academia Sinica in Taiwan.
The day before he left Hopkins in 1992 for RWJMS, Liu stopped to see his next-door neighbor. “I wanted to tell him that our enzyme turned out to be a drug target. I thought he’d be really impressed but instead he told me, ‘Leroy, in human history, before any major disease is cured, it’s prevented.’” Unnerved by the comment, Liu noticed how busy Talalay was.
“What’s going on?” he asked. Talalay was getting ready for a press conference with CNN and other media outlets. The pharmacologist had discovered that a component of broccoli could prevent cancer.
“Are you kidding?” Liu asked.
But it was no joke. Talalay was all over the news later.
“What Talalay had said was true. Prevention in many cases is more important than a cure. Many dietary components found in cruciferous vegetables, garlic, curry and selenium-rich foods have cancer preventive activities,” he explains.
“This field is still in its infancy. Perhaps, I shall follow the wisdom of my friend Talalay and start working on cancer prevention,” which is good news for the millions of people fighting or fearing cancer.