By Harrison Wein

On the Front Page...

Top cancer researchers from across the United States and Japan gathered at the Natcher Conference Center for 2 days in early March to celebrate 30 years of cooperation in cancer research between the two countries. The symposium, sponsored by the Japan Society for the Promotion of Science and the National Cancer Institute, highlighted some of the great progress in the field of cancer research during the long course of this cooperation, and outlined new directions for future progress.

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Dr. Joe Harford of NCI pointed out in introductory remarks that this is the most longstanding of NCI's bilateral international research programs. "The longevity of the program speaks volumes for how much we value this type of international cooperation," he said. "The fact of the matter is that cancer is a common enemy that does not recognize international borders."

Dr. Masaaki Terada, president emeritus of the National Cancer Center in Japan, put the symposium in context by outlining some of its history. He traced the beginnings back to the Japan-U.S. Committee on Scientific Cooperation held in Washington, D.C., in 1962. The 9th International Cancer Congress was subsequently held in Tokyo in 1966, but a formal relationship between the two cancer research communities was initiated in 1971 with a conversation between Dr. Frank Rauscher, then director of NCI, and Dr. Tomizo Yoshida, director of the Japanese Foundation of Cancer Research's Cancer Institute. A 1973 meeting in Hakone laid the groundwork for a formal Japan-U.S. Cooperative Cancer Research Program, and the first joint meeting was held in 1974 in Hawaii to establish an implementation framework. Since then, the program has held 265 seminars and had more than 500 exchanges of researchers to enhance international cooperation and strengthen both research programs.

Keynote speaker Dr. Robert Weinberg spoke about the cellular mechanisms leading to human tumor formation.

Dr. Robert Weinberg of the Whitehead Institute and the Massachusetts Institute of Technology gave the first keynote address, outlining the cellular mechanisms that lead to human tumor formation. He pointed out that there are at least 110 different kinds of human cancers. Countless genes have been implicated in these different cancers over the past several years. He wondered if researchers could define any universal laws about how cancers form. "Will there be any rhyme or reason to this?" he asked. "Perhaps there are some universal laws about all kinds of human cancers."

To this end, Weinberg identified five distinct regulatory pathways that he said must be disrupted to induce a human tumor. He went on to describe the approaches his laboratory is taking to recreate the early steps in human breast cancer formation and metastasis.

"One of the greatest determinants of whether tumor cells can proliferate is how efficiently they can recruit stromal cells," he said, referring to the supporting cells in surrounding tissue. "We need to look beyond the boundaries of the individual cells to see how they are interacting with their neighbors," he explained, concluding, "If we wish to understand all the rules governing cancer tumor formation, we have to consider all the cells, all of which contribute in essential ways to tumor formation."

The other keynote speaker, Dr. Julie Buring of Brigham and Women's Hospital, is an epidemiologist who gave a different perspective on cancer research, addressing the question of why there are often discrepancies between observational studies and randomized trials.

Dr. Julie Buring spoke about discrepancies between the results of observational studies and clinical trials.

She first outlined the differences between observational studies, where the selection of participants is done on the basis of a person's disease status (called a case control study) or on the basis of their exposure status (called a cohort study). She contrasted these types of studies to intervention studies, where exposures (say to a potential medicine, for example) are determined by investigators. The best-known type of intervention study, the randomized clinical trial, is considered the gold standard of clinical research studies.

"Sometimes, an observational study is the only feasible or ethical approach," Buring explained. For instance, researchers couldn't ethically administer a suspected carcinogen to some people to see if they developed cancer. But there are inherent limitations in observational studies, she said. "People who select one way to live also select others."

Buring gave some highly visible examples to illustrate how observational studies and randomized clinical trials could have different outcomes. One was the relationship between beta-carotene and cancer. "In animal laboratory studies," she explained, "beta-carotene could block the carcinogenic process and inhibit specific tumor growth." There was also, she said, a large body of observational epidemiological evidence associating diets of fruits and vegetables with lower risk. Many believed this evidence pointed to beta-carotene.

But in trials, beta-carotene showed no benefit, and actually increased the risk of lung cancer among heavy smokers. People may have made an incorrect leap to one specific agent, she explained. It could have been the wrong agent, or maybe there was a loss of synergy with other nutrients in the diet. Maybe it was for too short a duration, she offered as another explanation. Or that blood levels of beta-carotene in the study were much higher than seen in observational studies. As for the smokers, it turns out that in the oxidative environment brought about by smoking, high doses of beta-carotene actually created harmful products.

Buring also recounted the recent findings from Women's Health Initiative studies on hormone replacement therapy (HRT). Many doctors had been giving their patients HRT based on observations, she explained, and some thought it was actually unethical to conduct a randomized trial and deny the benefits of these hormones to control groups.

But it turned out that the trials had to be stopped early because the risks of using these treatments for extended periods outweighed their benefits. There were many possible reasons for the unexpected results. Women taking HRT in the observational studies may have been living healthier lifestyles and seeing their doctors more often, for example. Unforeseen or "confounding factors" like these can cause a clinical trial to return unexpected results.

Many people get frustrated with discrepancies between studies, Buring said, particularly when the media hypes contradictory conclusions. But she argued that these discrepancies aren't necessarily a sign of bad studies. "Discrepancies may mean the system is working," she said. "This is exactly why we do trials. Apparent discrepancies are not necessarily contradictory or wrong; they may be looking at different questions."

Buring concluded that "Neither a reliance on randomized clinical trials nor observational studies is appropriate. All of us together are needed to answer a question."

The sessions that followed featured several scientists from both Japan and the U.S. describing their research progress. Highlights included Dr. Peter Jones of the University of Southern California speaking about promising new cancer drugs now in clinical trials that work by affecting the DNA methylation patterns in tumor cells. Dr. Yoichi Furukawa of the Institute of Medical Science in Tokyo outlined his laboratory's efforts to identify novel molecular targets for the treatment of human cancers. And Dr. Yokiko Gotoh of the University of Tokyo described a complex web of phosphorylation events that regulate cell death.

Dr. Steven Rosenberg, chief of NCI's Surgery Branch, closed the meeting by describing some exciting work in which NCI intramural researchers have explored immunotherapy as a way to treat cancer. After years of testing many approaches, his laboratory has found the greatest success in what he called a passive, or adoptive approach. Rather than directly immunizing the patient with tumor antigens — a strategy researchers had been pursuing for many years with mixed success — they ablated the patients' own immune system and replaced it with T cells selected for their avidity for tumor antigens. Thirty two patients have now been treated, and the results have been very encouraging; 50 percent of patients have shown an objective clinical tumor regression. NCI intramural researchers are now further exploring adoptive cell therapy.

NCI director Dr. Andrew von Eschenbach closed the symposium, remarking that the collaboration between cancer researchers in the U.S. and Japan has contributed substantially to the phenomenal growth in our understanding of cancer. He thanked scientists on both sides of the Pacific who serve on the coordinating committee for the program and those individuals at the Japan Society for the Promotion of Science and NCI who provide ongoing leadership.

Enjoying a cake to celebrate 30 years of cooperation in cancer research are (from l) Dr. Tomoyuki Kitagawa, Dr. Takashi Tsuruo, Dr. Snorri Thorgeirsson, Dr. Joe Harford, Koji Nakanishi, Dr. Michaele Christian, Dr. Masaaki Terada and Dr. Ed Trapido.