© 1998 by Oxford University Press
Beginning with the premise that little progress has been made in the last 40 years in the treatment of metastatic colon cancer, the meeting's organizer, Lee M. Ellis, M.D., a surgeon and cancer biologist from the University of Texas M. D. Anderson Cancer Center, Houston, said, "I was hearing about all the tremendous advances in our understanding of basic mechanisms of cancer progression and metastasis, but was frustrated with the fact that few, if any, of these advances were making any impact in the care of our patients with metastatic colon cancer. Nearly all patients with metastatic colon cancer will die of their disease and as clinicians, we do very little to impact the natural history of this disease."
"I thought it was important to bring together clinicians, basic scientists, and industry, not only to share information but to optimize informal interactions between the participants," he continued.
The meeting began with a few grim reminders -- that colon cancer is the fourth most common cancer and the second highest cause of death among cancers. Although the trend in 5-year survival rates for colon cancer has improved over the years (50% in 1974-1976 versus 63% from 1989-1994), the vast majority of patients who develop metastatic colon cancer die within 2 years -- at a rate of about 50,000 a year in the United States.
Several speakers observed that the overall increase in survival reflects improvements in surgical techniques, rather than any significant advances in treatment or early detection. Edward M. Copeland III, M.D., a surgeon from the University of Florida College of Medicine, Gainesville, said that surgical removal of the tumor remains the best choice for treating metastatic disease.
Adjuvant chemotherapy has been shown to be of some benefit to patients with stage III (node positive) and advanced disease -- with 5-fluorouracil (5-FU) plus either levamisole or leucovorin being the therapies of choice. 5-FU has been in clinical use since the late 1950s. The added benefit of levamisole and leucovorin was confirmed in the early 1990s.
However, chemotherapy for metastatic disease has only a small effect on survival -- tumor response rates are generally 20% or less.
"During my 30 years of practice, the technical treatment of the primary cancer has improved, but the biological treatment remains to be exploited," said Copeland.
Drug Targets
One popular drug target is the protein kinases, a family of over 1,000 cellular proteins that activate or inactivate other proteins by attaching a phosphate group. Because the kinases play key roles in communicating from outside the cell to the nucleus -- including signals for cell division -- and are frequently overexpressed in tumors, kinase inhibitors are promising candidates for therapeutic targets. Also, several research groups are focused on defining the molecular pathways involved in carcinogenesis.
Kinases such as Src, focal adhesion kinase (FAK), epithelial growth factor receptor, and cyclin-dependent kinases (cdks) are examples. Researchers at Zeneca Pharmaceuticals in Wilmington, Del., are testing an inhibitor of epithelial growth factor receptor in early human trials, and the National Cancer Institute is sponsoring phase II trials with a cdk inhibitor, flavopiridol. Another researcher, Tona M. Gilmer, Ph.D., from Glaxo Wellcome in Research Triangle Park, N.C., noted that because abnormal kinase activity frequently results in resistance to apoptosis, her group is screening the company's vast drug library for kinase inhibitors that promote apoptosis.
Some speakers brought new biological approaches to old genes -- K-ras and p53 discovered nearly 20 years ago. The K-ras protein (the product of an oncogene over-expressed in greater than 50% of colon tumors) is active when a chemical group, farnesyl, is attached to one of its ends. One strategy championed by Bristol-Myers Squibb, New York City, and Merck & Co., Inc., Whitehouse Station, N.J., is to synthesize molecules, farnesyl inhibitors, that block that attachment.
Another group from Onyx Pharmaceuticals in Richmond, Calif., using a novel tack to capitalize on the under-expression of normal wild-type p53 (the product of a tumor suppressor gene inactivated in more than 70% of colon tumors), has designed an adenovirus that kills p53-deficient cells. Human phase I/II trials are under way.
Researchers are also looking for ways to increase the response rate of drugs currently in use. One way is to use the molecular profile of a person's tumor to guide treatment. Stanley R. Hamilton, M.D., from M. D. Anderson took advantage of two completed Eastern Cooperative Oncology Group phase III studies where 5-FU treatment was compared to other drugs. Knowing that only 15% of the patients in the trials responded to the 5-FU, he wanted to see whether specific alterations in a patient's chromosomes would predict which patients did well.
In a study not yet published, Hamilton found that two markers were predictive of successful 5-FU treatment. By analyzing 516 tumor blocks for a panel of genetic alterations, he found that overall survival was better if the 18q chromosome arm was intact. In addition, patients with microsatellite instability responded better to 5-FU treatment. (Microsatellite instability refers to mutations in repeated stretches of DNA sequences, usually caused by mutations in mismatch repair genes.) However, p53 status was not predictive of outcome.
A similar, but more technically sophisticated approach to using the tumors' molecular profile to guide treatment involves microarrays -- small glass chips embedded with small pieces of thousands of genes. In a collaboration between David Mack, Ph.D., head of genomics research at Eos Biotechnology, South San Francisco, Calif., Arnold Levine, M.D., president of Rockefeller University in New York, and researchers at the Peter MacCallum Cancer Institute in Melbourne, Australia, genes were identified that were expressed at abnormal levels in tumor cells compared to normal cells.
Matched Pairs
To identify those genes, Mack measured the expressed genes (in the form of messenger RNA) in matched pairs of normal and staged colon tumor tissue from NCI's Cooperative Human Tissue Network. By hybridizing fluorescently tagged messenger RNA to gene chips containing pieces of more than 40,000 human genes, they were able to identify genes that had a higher or lower level of expression in tumors compared to normal matched tissue.
Mack and his colleagues then used those genes to probe preserved colon tumor tissue from colon cancer clinical trials in Melbourne where both the treatment and outcome were known. A series of small sections from hundreds of preserved tumor blocks were probed with the candidate genes discovered by microarray analysis to see which markers can predict the patient's outcome. The experiments will be completed in the next several months and Mack is hopeful that similar collaborations will lead the way to identifying patients with a distinctive molecular profile who will be responsive to particular treatments.
Not only is it likely that microarray technology will play an important role in tailoring treatment options, but those same genes that Mack found to be expressed at higher or lower levels in tumors compared to normal cells, may prove useful as molecular markers for early detection or for predicting prognosis.
Although nothing presented at the meeting will be likely to help patients with metastatic disease tomorrow, there is certainly no lack of promising options. In fact, one of the speakers who spoke about the changing paradigms of clinical trials noted that the accelerated growth of new drug targets, new drugs, and new biomarkers to test will require many more patients for clinical trials. Eric K. Rowinsky, M.D., for the Institute for Drug Development in San Antonio, Texas, said that "since large phase III evaluations will be required for a massive number of new anti-proliferative agents, it is critical that our existing clinical trial infrastructure, in which less than 5% of all patients participate in clinical trials, change also."
All things considered, that seems like a nice problem.
-- Nancy J. Nelson
Quest for New and Better Colon Cancer Treatments Picks Up Steam
Investigators from all parts of the country met in San Diego last month to share creative attempts at exploiting the windfall discoveries of cancer-related genes and their biological pathways to advance the cause of colon cancer diagnosis and treatment.
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