International Researchers Take Pinpoint Aim at Cancers by Gina Shaw Surgery, radiation, chemotherapy: For years, these options have been the one-two-three punch of cancer treatment. Either singly or in combination, they have been virtually the only therapies available to cancer patientsóand although theyíve saved and prolonged many lives, scientists continue to seek out other, less drastic options. Could targeted therapiesótreatments designed to directly attack specific types of cancers while leaving healthy cells undamaged, unlike the blitzkrieg attacks of traditional radiation and chemotherapyóbe just around the corner in some cases? New research offers promise that these options could be closer than ever. "Over the last few years, the hope of targeted therapy has long been that it would preferentially attack cancerous tumors and leave the normal tissue relatively unscathed," said Dr. Michael Gordon of the Arizona Cancer Center, who moderated a session on targeted therapies at the May 2001 meeting of the American Society for Clinical Oncology (ASCO). "Now, weíre starting to see a significant indication that the potential for targeted therapies is being realized." In some case s, he noted, progress is being made in treating types of tumors that had previously been very resistant to treatment. So what are targeted therapies, what do they do, and what kind of cancers might they treat? Blocking the Signal One targeted treatment that appears to hold a lot of promise for several types of cancerósome rare and some commonóis a substance called STI-571, an orally administered "signal transduction inhibitor." Signal transduction inhibitors interfere with the enzymes that trigger cell growth. Think about using your cell phone. When youíre trying to place a call and something blocks communication between your phone and the nearest cell tower, you canít complete the call. For certain enzymes, STI-571 blocks the "call" from the membrane of a cancer cell to the nucleus, telling it to divide again. The signal never goes throughóso the proliferating cancer cell doesnít divide. Instead it goes through what scientists call "apoptosis," or cell death. No more cancer cell. STI-571 has this effect on at least two important cancer-causing elements. One is c-kit, a gene that causes the growth of cells in an unusual kind of tumor called a gastrointestinal stromal cell tumor (GIST), a cancer of the smooth muscles of the stomach. The other is bcr-abl, a gene product that is associated with chronic myeloid leukemiaóa far less unusual cancer. On May 10, 2001 the FDA approved STI-571, also known as Gleevec, for the treatment of chronic myeloid leukemia. Research into the drugís effect on GIST is still in its early clinical trials. Dr. Alan Van Oosterom, an oncologist at UZ Gasthuisberg KULeuven in Belgium, led a European team of researchers investigating just how high a dose of STI-571 is needed, and for how long, to effectively treat gastrointestinal stromal cell tumors (the stomach muscle cancers). One problem was that STI-571 only interrupts the signal in cells that are just about to divide, "so tumor cells which are not going to divide at that moment will not be hampered by STI-571," Van Oosterom said. "Only the cells about to divide will have the signal interrupted and will die. Cells which are not about to divide will not have their signal interrupted and will remain tumor cells in the body." Doctors theorize that this means a patient will have to continue taking the drug for a long time to kill all the cancer cells. Two promising studies presented at the ASCO meeting indicated that STI-571 has great potential benefit in treating GIST tumors. One team, led by researchers at the Oregon Health Sciences University in cooperation with scientists from Philadelphia, Boston, Finland, and Switzerland, reported that STI-571 produced an 89 percent clinical improvement in patients with GIST. In Van Oosteromís study, a cooperative venture of the European Organization for Research and Treatment of Cancerís Soft Tissue and Bone Sarcoma Group, scientists wanted to know how high a dose of STI-571 most patients could tolerate before side effects became intolerable. At the highest dosage given in the studyó1,000 milligramsóside effects that included nausea and vomiting, skin rash, and swelling of the extremities became so bad that most patients couldnít handle them, and the dose was dropped down to 800 milligrams. But the European researchers noticed something unusual about STI-571ís side effects. "If you keep patients on the drug for about eight weeks, you can also ëtalk them throughí the side effects. They accept and tolerate them and the side effects seem to fade and go away," Dr. Van Oosterom said. "Normally, in chemotherapy, side effects increase over time and become more intolerable. Thatís the strange thingóIíve never seen this before. It might be that the normal tissues start to understand the trick and then do something so the side effects fade away. Iíve learned more from this drug than from other drugs in the past, and Iíve been in drug development for over 30 years." Van Oosterom was amazed by STI-571ís effectiveness. "All the patients we saw in our department [in Belgium] and in London and in Rotterdam had quite progressive cancer. Nearly all of them had taken a lot of cytotoxic drugs." For example, with chemotherapy, "many of them had disease that had metastasized to their liver, and most also had major complaints of their disease." In the "old days," Van Oosterom said, about 10 percent of patients with GIST would respond to traditional treatments like chemotherapy, while in the remaining 90 percent, the cancer would continue to progress. But with STI-571, the results appear to be completely the reverse. "Only 10 percent do not respond. That was the magic thing of this whole study. In 70 percent of the patients you see the tumors really decreasing, and in 20 percent you see stabilization, so the disease does not advance any longer." Six weeks after presenting his study findings at ASCO, Dr. Van Oosterom said that the numbers are the same. But the potential benefits of signal transduction inhibitors donít stop with GIST and chronic myeloid leukemia, Dr. Van Oosterom believes. "Thanks to the Human Genome Project, we now know about 21 percent of the genes that are involved in signal transduction. If we know, for many diseases, where the signal transduction genes which are their driving force go wrong, then we can have the industry look more into these mechanisms for other cancers," he said. "That means we could do a lot more for cancer patients in the future." The next step, at least for research into STI-571ís effectiveness in GIST, is a large international Phase III study that will compare two doses of the drug: 400 milligrams and 800 milligrams. Researchers hope to recruit 800 patients in the United States and 800 in Europe for a total of 1,600 patients on both sides of the ocean. "At the ASCO meeting next year, we will have the answer as to whether the dose is importantóand I think it is," said Van Oosterom. "I think what will happen is that patients will need to accept a little higher toxicity"óin other words, side effects like nausea and headacheó "for a higher and faster response." He predicts that the U.S. Food and Drug Administration will approve STI-571 as a treatment for GIST by November of next year. "So then the drug will be available everywhere." Cutting Off the Blood Supply "Within a year, if all goes well, the first cancer patient will be injected with two new drugs that can eradicate any type of cancer, with no obvious side effects and no drug resistanceóin mice." With these words in an article in the May 3, 1998, edition of the New York Times, science writer Gina Kolata caused an international uproar over work being done by Dr. Judah Folkman of Boston Childrenís Hospital and its potential to "cure" cancer. ("Cure" is a four-letter word, say many cancer researchers.) The overhyped Kolata story sparked a media feeding frenzy, including a U.S. News and World Report cover headline "Meet the Mouse that Beat Cancer." Of course, the truth was far more complicated, and eventually the floods of patients calling to request the "cancer drug" abated. But the research, involving a series of compounds called anti-angiogenesis agents, continued. Although such compounds arenít the magic bullet of cancer treatmentómost cancer researchers donít believe there is any such thingócontinuing research seems to indicate that these agents may be a very important anti-cancer weapon. What do anti-angiogenesis agents do? Put simply, they cut off the blood supply to a tumor by inhibiting the formation of new blood vesselsóa process known as angiogenesis. They work to starve the tumor out by cutting off oxygen and energy. But treating cancer patients with anti-angiogenesis agents promises to be a complicated and individualized process, acco rding to British researchers conducting early clinical trials on one such agent, a drug known by the alphabet-soup name of HuMV833. "The principal growth factor responsible for the development of new blood vessels in cancers is vascular endothelial growth factor (VEGF)," said Dr. Gordon Jayson of Christie Hospital in Manchester, United Kingdom, lead author of the study, which also involved hospitals in Austria, Belgium, the Netherlands, Sweden, and the United States. "VEGF is also known as vascular permeability factor because it controls the leakiness of blood vessels." This is important, he said, because proteins and nutrients can leak into cancers through blood vesselsóand this, in turn, allows further growth of the tumors and the blood vessels feeding them. When testing HuMV833 in patients, Jayson and his colleagues found that it did, indeed, reduce the "leakiness" of the blood vessels. "In the patients in this study, we observed reductions in vascular permeabilityósupporting the theory that our antibody was working through an inhibition of VEGF activity," he said. And these results did translate to improvements in at least some patients in the study. The 20 patients involved all had advanced cancers, which Jayson noted would be expected to lead to further deterioration of their condition and progression of their cancer within a few months. Three of the patients in the study instead had their condition stabilize, and one woman had a significant reduction in her ovarian canceróa surprise to the researchers, who expected patientsí conditions to stabilize but not to reverse. "Stabilization of disease is difficult to interpret and we should be cautious," Jayson warned. "However, one of our patients with colon cancer whose disease had progressed despite treatment has now had stable disease for a year and is feeling very well." But itís not that simple. First, of course, the study was very small. Second, the international research team found that tumors react differently to the agent not only from patient to patient, but even within the same patient. In other words, separate tumors within the same patient might react entirely differently to a dose of the drug, so determining how much of a drug to give a patient could be very complicated. The standard methods of doing a clinical trial for a new drug might not apply in this case, Jayson said. "We have seen significant variation within and between patients in how their tumors take up the drug and respond biologically," said Jayson. "We need to redesign trials to compare escalating doses within each patient, not between patients." Halting Bone Destruction Many cancers ultimately spread to the bones of the body in whatís called bone metastasis. Breast cancer, myeloma, and prostate cancer, for example, all can eventually involve the bones, literally eating holes in the framework of our bodies. "Our bones are in a continuous state of flux as bones are being formed and destroyed. The skeleton is always remodeling itself," said Dr. David Dearnaley of the Institute of Cancer Research and Royal Marsden NHS Trust in Sutton, United Kingdom. In a disease such as osteoporosis, in which bone density is lost, this remodeling process is out of synch. "Thereís more bone destruction than formation." In recent years, scientists have begun to investigate whether a group of drugs that effectively combats osteoporosis by reducing bone destruction might also have some effect in halting bone metastases in cancer patients. These drugs, whose names all end in "onate" (clodronate, evandronate, zendronate) have shown promise in slowing bone metastases in breast cancer and myelomas, but until now they havenít been tested on men with prostate canceróthe most common cancer in American men other than skin cancers. Could clodronate and its pharmaceutical cousins be of benefit in treating this type of cancer, which kills 31,500 men in the United States alone every year? Doctors are hopeful, because in prostate cancer, the bones are the primary site of metastatic spreadófor some reason, prostate cancer seems to particularly like to attack the bones, and most prostate cancer patients eventually develop bone metastases. "If you can make the bones more resistant to the cancerís spread, that can potentially slow the cancer down," said Dearnaley, lead scientist on the first-ever study of clodronateís ability to prevent or slow bone metastases in prostate cancer. In Dearnaleyís study of 300 men with prostate cancer, those taking clodronate increased both their total survival rate and the time to progression of the disease in the bones by about six months. "Itís a very strong suggestion that this type of drug may have a role in prostate cancer," he said. "What we really need to do now is larger studies, with some of the more potent drugs now available." Clodronate has been around for 10 years and some of the other, newer -onate drugs are stronger. International Collaboration As cancer treatments become more individualized and specialized, through the discovery of specific enzymes, genes, and other factors that appear in the growth of certain cancers but not others, international collaboration in cancer research becomes ever more important. "One of the most important steps in the development of a new agent is the phase III [randomized controlled] trial in which patients are randomly allocated to receive the standard treatment or the new treatment. This is the only way to determine whether a new treatment is better than an old treatment," said the U.K.ís Jayson. "The statistical design of these trials is crucial and frequently dictates that several hundred if not thousands of patients are enrolled in a trial." Recruiting that many patients for a studyóespecially if it involves an unusual type of cancerócan be difficult, taking months and even years. Remember STI-571? Because it only blocks the "cell divide signal" in GIST (c-kit) and chronic myolegous leukemia (bcr-abl), it wouldnít make any sense for researchers to recruit a patient with, say, prostate cancer to participate in a study involving STI-571. So for each of these targeted, specialized therapies, there is a limited pool of patients who can be involved in studies. But when cancer research goes global, that pool gets bigger. "In the U.S., [getting enough patients] can be achieved through interstate collaborations, but in Europe it requires international collaborations," Jayson noted. "There is increasing discussion about European-U.S. collaboration for phase III trials, and this is vital if questions of efficacy are to be determined. I think that international collaboration is increasingly recognized as an important contribution to drug development and cancer treatment." Gina Shaw is a freelance medical writer in Washington, D.C.