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Getting to the Roots of Cancerby Ruth SoRelle, M.P.H. 
(l-r) Drs. Jenny Chang, Michael Lewis and Jeffrey Rosen Many times, women with breast cancer seek care at the taxsupported Ben Taub General Hospital very late in their disease. Their tumors are too large to deny, painful and deadly evidence that something has gone wrong in their breasts and in their ability to access treatment. Then these women then do something remarkable. They become part of the team from the Lester and Sue Smith Breast Center at Baylor College of Medicine, allowing scientists to study the tissues from their breast tumors. Their cooperation enabled Smith Center researchers Drs. Jenny Chang, Michael Lewis and Jeffrey Rosen to forge new understanding of the cells that initiate breast tumors and to study new treatments that can eradicate these stubborn "roots." "These patients make it possible for us to study these cancers. They are among the populations of patients who are most willing to help. Their contribution is huge," said Lewis. Lewis, associate professor in the Breast Center; Chang, medical director of the Breast Center, and Rosen, professor of molecular and cellular biology at BCM have made new inroads into understanding the tiny subpopulation of cells in the tumor that may have started the malignant process itself. Different kind of stem cellThey are not classically stem cells, but they do reproduce as though they were stem cells. When they divide, one of the daughter cells is identical to the mother and the other has become more differentiated. They can selfrenew, maintaining a population of cells. These are all criteria defining stem cells. "These patients make it possible for us to study these cancers. They are among the populations of patients who are most willing to help. Their contribution is huge." As the BCM researchers have found, they are also stubbornly resistant to the most common forms of anticancer drugs. Many cells in a tumor are resistant to treatment, said Rosen. "In some cases, that resistance is acquired as the tumors are exposed to different drugs. However, the cells that don't respond to the initial treatments are, we think, related to cancer stem cells." "Normal stem cells are rare and quiescent, which means they do not divide a lot. However, not all cancer stem cells in tumors have to be rare and they don't have to be quiescent," said Rosen. Collaborating on the attackPutting together a plan of attack on these cells is a collaborative venture. "We sought to prove whether these cells exist in humans," said Chang. That venture was made possible by the patients themselves, including those at Ben Taub, who agreed to let some of their tumor tissue be used in the studies. In a report in the Journal of the National Cancer Institute, the researchers showed that they could isolate this subpopulation of tumorinitiating cells in laboratory and increase their numbers. In short, they proved these cells exist and continue to exist throughout the life of the tumor. "Physicians who treat patients do not find this surprising," said Chang. "We give chemotherapy. We know we can shrink the tumor down from a large cancer to a little nubbin that is different from the rest of the cancer that shrank. That nubbin can grow into a large tumor again, almost instantaneously." Identifying stem cells early or even preventing those changes that lead to cancer might mean, some day, that women no longer seek care too late, when their breast tumors are too large to cure. That is why for some patients, chemotherapy can control the disease, shrink the tumor, improve quality of life, but it has little impact on how long a woman lives. "It is hard to think that some of the treatments the patients get do not make a difference to their longterm survival," she said. Targeting the beginningThe BCM researchers want to see how these cells contribute to breast tumorresistance to chemotherapy. The generosity of the patients at Ben Taub gave the scientists the opportunity to evaluate tumors before the women underwent chemotherapy and after. That way they could profile the cells left behind. "Using genomics, we were able to show that there was a characteristic gene profile of these cells," said Rosen. "That led us to ask: ‘What accounts for these properties and why are these cells more resistant?'" These tumorinitiating cells take different paths from other cancer cells. In doing so, they elude normal chemotherapy. That indicates that a more important indicator of a whether a tumor responds to treatment is not so much how the drugs shrink it, but how many of these tumorinitiating cells are left after treatment, Rosen said. "Tumor size alone is not a good indication of response," said Rosen. "The percentage of tumorinitiating cells left behind might be." Going after the initiatorsTo attack these cells, the researchers looked for pathways within the cells—those that contain the messages the cells need to survive. Then they sought drugs to block those pathways. In a recent study, Chang led a trial that used a drug that blocked the Notch pathway, which governs the fate of a cell when it divides. The Notch pathway is involved in the division of both normal and cancer cells. Using a drug that blocks activity of an enzyme called gammasecretase, the researchers were able to eradicate human tumors grown in mice. In studies of women who underwent treatment with the gamma secretase inhibitor and chemotherapy, the population of tumorinitiating cells was depleted as well. "It is good but not enough," said Chang. Now she and her colleagues are seeking funding for a project that combines treatment with different tumorinitiating cell inhibitors. Among those are a molecule called Stat3 (signal transducer and activator of transcription3). In this, she and her colleagues are collaborating with Dr. David Tweardy, professor of medicine and chief of the division of infectious diseases at BCM, who studies Stat3. They are also studying other potential inhibitors of these deadly cells. Collaborative effortsThis kind of science does not exist in a vacuum. In addition to their BCM collaborators, the researchers are also part of a consortium led by The Methodist Hospital and includes The University of Texas Health Science Center at Houston. With a fiveyear, $11.5 million National Institutes of Health grant, they hope to find ways to identify these cells more definitively and analyze the pathways that are critical in order to develop even more potent drugs against them. The UT and Methodist investigators are establishing bioinformatics and mathematical models that can demonstrate how these cells behave in treated and untreated tumors, enabling the researchers to make predictions about the effectiveness of treatments before they are tried in patients. Longtime collaborator and stalwart in the field Dr. Max Wicha, director of the University of Michigan Comprehensive Cancer Center in Ann Arbor, said the BCM team has done some pioneering work. "The basic work of Rosen demonstrated that these cells were resistant to treatment," he said. Then, the work by Chang and her collaborators showing that the numbers of tumorinitiating cells actually increased after standard chemotherapy was pivotal, he said. He said an alliance is now looking at testing a whole series of tumorinitiating cell inhibitors. How it startsLewis hopes to understand what early changes contribute to changes in the architecture of the cells that then allow them to become cancer. "Maybe we can identify them early and get them when they are 100 percent curable or even prevent them in a safe way," he said. That reflects on the beginning—the patients. Identifying stem cells early or even preventing those changes that lead to cancer might mean, some day, that women no longer seek care too late, when their breast tumors are too large to cure. Rosen holds The Charles C. Bell, Jr. Professorship in Cell Biology. Chang holds a Dan L. Duncan Chair. |
FeaturesThe Future of Health Care Starts at Med High Emergency Medicine: The Art of Juggling A Quarter Century of Invention at Baylor College of Medicine "Passport" Gives Childhood Cancer Survivors Entry into Adult Healthcare Dan L. Duncan Cancer Center Educates Through Entertainment Getting to the Roots of Cancer NewsDr. Paul Klotman: BCM's New Top Man Dan Duncan Leaves Solid Foundation for BCM's Research Future DeBakey Library & Museum Showcases Innovations of Pioneering Heart Surgeon SpotlightBIPAI Doctor Seeks to Serve in Africa Space Medicine Takes Medical Education Across New Frontiers Quest for a Gene Opens New Door in Personalized Medicine BriefsOut of This World Science Experiment Generates International Interest Predicting the Progression of Alzheimer's Disease Pool to Receive Academic Clinical Professionalism Award The Pea Aphid and the Wasp Genome Development/AlumniBelieve in BCM Campaign Engages Campus Development BriefsNational Osteoporosis Foundation Honors Lawrences DeBakey Heart Center of BCM Benefits from Partnership Event Pink Ribbon House Project Celebrates Success Awards and Honor Wall Highlight Alumni Reunion 2010 The Road Ahead Promises Continued Success
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Volume 6, Issue 1, Summer 2010 |
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