LOUISIANA RESEARCH


	Lock & key Researchers at LSU's Pennington Center are developing a cancer treatment that may reduce the side effects of chemotherapy and the dangers of cancer spread. Modern cancer chemotherapy is a purveyor of both vast hopes and harsh realities to cancer victims. The drugs typically destroy both good and bad cells, making it difficult to kill the cancer without harming the healthy parts of the patient's body and adding immeasurably to their suffering. Patients lose hair, experience extreme nausea, and suffer through a gauntlet of new pains, digestive problems and weight loss. The reason: most cancer drugs are designed to kill the rapidly dividing and growing cells typical of cancer tumors, which means they also attack other rapidly dividing human cells, such as hair follicles and the stomach lining. While there are many chemotherapy drugs and each comes with a different battery of side effects, most chemotherapy patients can identify with the patient who summed up chemotherapy as a whole new way of looking at time: while most of us have gone through bad weeks when it felt like an achievement to make it to the next day, for him it became an achievement to make it to the next hour. On top of physical difficulties that range from skin rashes to weakness to diarrhea, patients must cope with the far-reaching emotional impact of dramatic changes in pain level, activities, independence and appearance. Enter scientists at the Pennington Biomedical Research Center, known worldwide for its expertise in nutrition and obesity. Center endocrinologists, in their pursuit of basic knowledge about nutrition-related chronic diseases, have recently patented a potential cancer treatment void of the wrenching side effects and rich with added benefits. Though the term is overused, "breakthrough" is an apt description of their discovery, especially in light of its potential to lighten the load associated with chemotherapy. Lock meets key The breakthrough occurred when two seemingly disparate pieces of work were thrust together, almost by happenstance. Pennington scientist Dr. William Hansel was at a scientific conference in Poland in 1996 when some colleagues gave papers mapping out the receptors for luteinizing hormone, called LH, on breast cancer cells. LH is a reproductive hormone released by the pituitary gland that stimulates the production of testosterone and estrogen and affects other sexual functions. Receptors are protein molecules located on or in cells that receive and interpret messages sent by hormones like LH. In women, for example, ovulation is triggered during the menstrual cycle when LH molecules bind to their receptors on healthy cells in the ovaries, changing DNA replication within the cells. Hansel's friends had discovered that these receptors look different on the outer membrane of breast cancer cells and that they rejected hormones that would have attached when the cell was healthy. It was the first time someone had described this process and, upon examination, Hansel had a flash of recognition. These hormone receptors, he realized, were like "locks simply waiting for a key to fit"-and he had the key-a special "conjugate hormone" that he had developed while researching functions of the pituitary gland. When he returned from the conference, Hansel and his research partner, Dr. Carola Leuschner, a biochemist, set to work on a new way of looking at an old problem. Quick results With a swiftness rare in the painstaking and incremental world of scientific progress, Hansel's team began using the key and lock to deliver, like a Trojan Horse, a deadly blow to breast, prostate, ovarian and testicular cancer cells. "Within a month we had results," Hansel recalls. "It killed cancer cells beautifully." Years before, while conducting unrelated research on the pituitary gland, Hansel developed a technique in his lab for destroying hormone-producing cells by welding a peptide onto a messenger hormone. Peptides, like proteins, regulate biological and cellular functions. When a hormone attaches to its receptor on a cell's surface, it delivers a message to the cell to produce another hormone or chemical product. Now, Hansel tested this conjugated hormone on cancer cells and their newly mapped hormone receptors. Specifically, Hansel joined Phor21, the membrane-destroying peptide, to a portion of CG, the hormone chorionic gonadotropin, which normally binds to receptors in ovaries, testes, prostates and breasts to signal the start of reproductive functions. In the lab, Hansel and his team learned that this Phor21-CG conjugate delivered the damage to unwitting receptors, breaking down the outer cell membrane and destroying the cancer cells with ruthless efficiency. What's more, because Phor21-CG doesn't gain its effectiveness by disrupting new, rapidly dividing cells, it should have fewer of the side effects so debilitating to chemo patients, such as nausea, body wasting and hair loss. An equally significant benefit may be the fact that a drug based on this conjugate could be used to seek out malignant cells commonly shed from primary cancer tumors. This process of shedding cells-called metastasis-is the most deadly feature of cancer. Doctors may shrink, kill or remove a breast cancer tumor, for example, only to battle months or years later tumors germinated from the shed cells that took up residence and formed new, deadly cancers in the liver, brain, lung, lymph system or bone. The potential promise of Hansel's work, and a reason for recent headlines, is that Phor21-CG could kill metastasized cancer cells more effectively than current treatments-tracking down and killing them in addition to the main tumor-while patients continue to look and feel as normal as possible during treatment. And if the drug is completely effective, the expected decline in return cancers would afford a much greater, post-treatment peace of mind. The power of collaboration Hansel and Leuschner are both quick to credit the other branches of the LSU system that collaborated on the research, especially the LSU AgCenter and the chemistry department at LSU. Dr. Fred Enright of the Veterinary Science Department at the AgCenter, Dr. Mark McLaughlin in chemistry and Dr. Marek Bogacki all contributed to the work. The collaboration has already resulted in a patent for the new drug and the treatment method (issued to the LSU AgCenter), thus securing the rights to future revenues should the drug prove effective and marketable to humans. "These are the most promising results I have ever seen in our lab," says Hansel, an assessment that gains considerable gravity upon consideration of the source. He spent 44 years at Cornell University working, learning, and advancing the field of reproductive biology, and has been at Pennington since 1990. Now 85 years old, he still has more interest in examining test results than relaxing in retirement. "I don't really like to fish or golf," he quips. Hansel is still in his lab early each day, and still more excited about the future of his research than the pleasures of retirement. Currently, he is mapping out the next steps of his research and enjoying some deserved help-the National Cancer Institute has accepted his work into its RAID program. The institute's Rapid Access to Intervention Development program supports promising work and researchers in their quest to gain approval for human clinical trials. The NCI is already manufacturing Hansel's conjugate in greater quantity for further lab studies and is working to create a manufacturing method to ramp up for human trials. The NCI will also assist in carrying out the dozens of toxicity and dosage tests of the drug in lab animals, all with an eye to completing an application to the U.S. Food and Drug Administration for the first human clinical trials, which could start as early as next year. Overcoming skepticism Hansel is a man of infectious enthusiasm, but his journey to this point of success in the lab was not all smooth. He recalls the first reaction of a colleague he called for help. "He said it couldn't be done. He said I couldn't get enough of the Phor21 peptide onto the cell to kill it by using the messenger hormone. So he gave me some cell samples to 'prove it won't work.' We used normal Chinese hamster ovarian cells, which don't have CG receptors, and the same type of cells with varying amounts of CG receptors artificially added to them. We saw the number of cells the peptide killed was directly related to the number of receptors on the cells-the more receptors a cell had, the easier the peptide killed it. Of course the normal cells without the receptors weren't harmed except at very high concentrations of the drug." Hansel worked for the next three years improving his lock-and-key mechanism, trying different messenger hormones and different killer peptides, finally settling on a conjugate of Phor 21 and CG, delivered by tail vein injections in lab mice. The results were striking. Hansel could kill nearly every breast, ovarian and testicular cancer cell with his conjugate. "But all that in vitro work (work done only in laboratory containers) languished until Carola came aboard," Hansel says. "She's the one who started up our test system in mice and devised the method showing that the conjugate kills metastatic cells. Ask her about the fireflies." Leuschner has a Ph.D. in biochemistry from the University of Hanover in Germany and, today, a new-found enthusiasm for fireflies. Leuschner needed to find metastasized cells-perhaps only a few-in livers, ovaries or other organs of mice and see if the drug killed them. In a stroke of creative insight, she learned she could borrow the gene that causes fireflies' tails to glow, called Luciferase, place it into human breast cells, and then grow them in mice. Later, when she examined entire livers, lungs, bones and lymph glands to find any cancer cells that had shed off and taken up residence in other organs, the cancer cells glowed. Using specialized sensors, Leuschner can spot as few as three living cancer cells in an entire mouse organ by this method. Comparing the organs of nontreated and treated mice was conclusive: the drug they were using killed metastasized cancer cells as well as cells in the tumors themselves. Chasing down metastasized cancer cells and killing them with peptides has become something of a research passion for Leuschner, who has no intention of abandoning the quest for effective cancer treatments anytime soon. "This has been extremely rewarding work," she says. "Developing a drug against cancer in itself is very exciting-and a great motivator." Hansel and Leuschner may soon add another arm of the LSU system to the partnership that has produced this lock-and-key approach to killing cancer cells. If the RAID program is successful, Hansel's team will gain FDA approval for the first trials with human volunteers, trials which are likely to take place at the LSU Health Sciences Center in New Orleans. While many scientists believe it is unlikely that there will ever be a single "cure" for cancer, developments like those at Pennington are making it more and more likely that medicine will make steady advances against the killer by using different drugs and different methods for different cancers. In the process, science may also shift the terrifying trade-offs of chemotherapy, leaving the hope to far outweigh the horror.