Finding a Better Way to Identify Bladder Cancer

Urothelial bladder cancer, the fourth most common cancer in men and the eighth most common in women, accounts for more than 54,000 new cases and 11,200 deaths annually. Cystoscopy and cytology, used to detect this transitional cell cancer in situ, have significant drawbacks, including relatively low sensitivity, patient discomfort, and infection risks. Now, a new U.S./European research consortium wants to create a simple, cost-effective, noninvasive diagnostic test to replace cystoscopy and cytology. Later this year, the consortium, which includes Yale University researcher Dario C. Altieri, will initiate multicenter trials to find which of seven recently identified molecular markers, alone or in combination, is the most accurate detector of bladder cancer. One of the most promising markers is survivin, an enzyme inhibitor of apoptosis (IAP) that is selectively overexpressed in human cancers and correlates highly with the disease but not with healthy tissue. The protein is produced by the gene survivin, the smallest member of genetic apoptosis inhibitors. In addition to bladder cancer, the protein survivin is abundantly found in cancers of the colon, brain, lung, skin, and others. However, it is generally not detected in normal tissue adjacent to the malignancies. Altieri, a pathology professor at Yale University School of Medicine, and a research team discovered survivin in 1997.1 In his latest research, Altieri's group has developed a 1-step system for detecting survivin in voided urine using a polyclonal antibody protocol.2 In this preliminary study, survivin was detected in the urine samples of all 46 patients with new or recurrent bladder cancer. In addition, survivin was not found in 32 of 35 patients who had been treated for bladder cancer but who also had negative cystoscopy results. None of the healthy volunteers or patients with prostate, kidney, vaginal, or cervical cancer had detectable survivin in their urine. "We are working on the commercialization of this simple test," Altieri said, adding that he and other researchers are preparing trials using larger patient groups. Bjorn Logi Bjornsson, a pathology professor at Lund University Hospital in Sweden, is organizing the U.S./European consortium. In a discussion paper distributed to potential consortium participants, Bjornsson says that he hopes by year's end multicenter trials can begin identifying which of the seven markers is the most accurate bladder cancer detector. The goal, Bjornsson wrote, is to derive a test mechanism with 95 percent sensitivity and 90 percent specificity, based on a mix of patients presenting symptoms suggestive of cancer in urology practice. In addition to survivin, other markers and tests include microsatellite alterations in urine sediment (MAUS); urinary hyaluronic acid and hyaluronidase (HA/Haase); BCLA-4 antigen; Due AUT2/Due ABC 3 dual-parameter immunoflow cytometry; Mcm5; and COX-2. Altieri and other researchers are still working to fully understand the mechanisms of how survivin and other apoptosis-blocking proteins work. Many researchers believe that these molecules proteolytically break down the cysteine protease caspase-3, thereby inhibiting caspase activity which, in turn, allows malignant cells to continue growing while making them resistant to stress and eventual death from radiation and chemotherapy. Other researchers believe survivin interferes with caspase activity through a totally different pathway. Regardless of the molecular mechanism, regulating survivin and other IAPs might well make malignancies more vulnerable to therapies. Survivin, then, holds promise both as a possible target for therapeutic intervention as well as a marker of cancer progression. Elsewhere, other investigators are exploring whether survivin in other bodily fluids can be a marker for other cancers. Ernst P. Rieber and an immunology research team at the Technical Institute of Dresden, Germany, for example, was able to detect significantly elevated levels of antibodies to survivin in the blood of lung cancer and colorectal cancer patients.3 The high prevalence of these anti-survivin antibodies, the researchers report, makes them "an attractive novel marker for the diagnosis of lung and colorectal cancer." The idea behind these other approaches, says Altieri, is to integrate and complement the cytology with more specific markers. "And survivin could be one of them, since survivin itself is selectively expressed in tumors and not in normal tissue." The Yale researchers are pursuing several avenues, including understanding the basic science of the molecule and its pathway. The group also has a strong interest in translational research, primarily diagnostic but therapeutic as well. "This is an academic lab, so we don't do screening of compounds," comments Altieri, "but there are two aspects of survivin that make it an attractive therapeutic target: it is selectively expressed in cancer and when you interfere with its function or expression, cancer cells die; it is essential for viability; [and] it is an essential gene." As for the upcoming multicenter bladder cancer test, whether survivin survives as the most reliable marker for bladder cancer remains to be seen. "You want several different institutions standardizing several different tests," explains Altieri, "and... see where the chips fall. Whatever the best marker proves to be, that will be a significant advancement." Ted Agres (tagres@usa.net) is a freelance writer in Washington, D.C. References 1. A.J.S. Rayl, "Survivin in 3-D," The Scientist, 14[16]:23, Aug. 21, 2000. 2. S. Smith et al., "Urine detection of survivin and diagnosis of bladder cancer," JAMA-The Journal of the American Medical Association, 285[3]:324-8, Jan. 17, 2001. 3. J. Rohayem et al., "Antibody response to the tumor-associated inhibitor of apoptosis protein survivin in cancer patients," Cancer Research, 60:1815-7, April 1, 2000.

Finding a Better Way to Identify Bladder Cancer

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