No Cure Yet, But Success at an Early Stage

Using tools no more complicated than a microscope, a calculator and some common sense, cancer researchers at Harvard Medical School have pinpointed a vital step in the growth of malignant tumors in the human body.

Led by Assistant Professor of Pathology Donald Ingber and Professor of Anatomy and Cellular Biology M. Judah Folkman, the theoretical part of the research resolves a longstanding clinical question in the study of tumors: rather than being "born" with the capacity to cripple their host, bodily tumors acquire that ability sometime in the early stage of their development.

In other words, the researchers found, bodily tumors are harmless until they undergo a deadly transformation which pumps them full of nutrients and changes them from underfed weaklings into potent centers of cancerous activity.

This theoretical research is important in its own right: the New England Journal of Medicine gave these findings top billing in its January 3 issue. But the work holds even more promise now that another group of Harvard scientists has stumbled across a drug which prevents this transformation in the first place.

The proposed treatment, a synthetic version of an uncommon fungus known as fumagillin, has already shown evidence of halting cancerous lumps before they can send fatal offshoots to nearby lymph nodes or other vital organs. Laboratory animals subjected to this drug suffered from no harmful side effects associated with most common cancer treatments such as radiation therapy.

Together, these two discoveries, which came within months of each other at the end of last year, may change the direction of the entire cancer research industry, medical experts say.

"We hope this paper will stimulate others into looking into this," says Noel Weidner, a surgical pathologist at Brigham and Women's Hospital and a co-author of the New England Journal paper. Weidner's group is the only one at Harvard--and one of only a few in the world--currently studying angiogenesis, the sudden and dangerous transformation of benign tumors into malignant beasts.

The Medical School research has already gone beyond academic circles and penetrated the ranks of corporate cancer laboratories, Ingber says, as many companies are beginning to focus their anti-cancer divisions on the tumor-repressing approach.

"It opens up a whole new frontier in cancer therapy," says Ingber, who co-authored a December paper in Nature which identified the fumagillin fungus as an anti-tumor agent.

Besides helping the fight against cancer, the researchers say, the work may also potentially have applications to combatting other diseases, such as arthritis.

Nipping Tumors in the Bud

The fundamental scientific concept underlying the research is wonderously simple: tumors cannot grow unless they are well-fed with blood. In most cases, a normal cell which has somehow turned cancerous can multiply and divide about a million times before it "suffocates," unable to survive on the nutrients supplied to the original cell.

Folkman likens this tumor expansion process to the construction of an apartment complex on the spot where a lone house once stood. The plumbing and electricity--meaning the cell's blood--must be improved dramatically, since the apartment's residents cannot survive on the much fewer resources of the old house.

If the tumor manages to coax nearby blood vessels to come to its aid, it can continue on its growth pattern past the "apartment complex" stage, ballooning up from the size of a pinprick to that of a golf-ball or even larger.

"That's very dangerous," Folkman says. "That's when the tumor can grow exponentially." Even more importantly, he says, the newly-recruited blood vessels allow the tumor to send out offshoots known as metastases, which travel through the circulatory system until they lodge in vital organs such as lymph nodes, the lungs, brain or sexual organs.

Wreaking such havoc on the body is impossible without the help of local capillaries, the Harvard group found. If a tumor is unsuccessful in recruiting nearby blood vessels, it quickly starves, remaining a dormant and harmless lump of renegade cells surrounded by the body's normal cells.

Although a tumor must clear about 15 biological hurdles before metastasis occurs, scientists have become convinced that tripping up the tumor is easiest and most effective at this early stage.

Wonder Drug?

Armed with the theoretical background of how tumors work their way through the body, researchers are now fine-tuning their lab skills in an effort to stop real-live cancers.

Rather than excising the organ which is playing host to the tumor--often a dangerous or impossible procedure--the Harvard researchers found that they could inject a drug to halt the growth of blood vessels near the tumor, thus starving the cancer.

Finding such a drug wasn't easy. In fact, by Ingber's account, the discovery came as a stroke of luck.

"It was serendipity," he says. "We standardly have millions of cells growing, and you have to keep them sterile. This one day, I happened to have a contaminant."

The contaminant turned out to be a fungus which, upon close inspection, had caused nearby cells to become rounded. Such rounding intrigued Ingber, since rounded cells tend to crowd out or stunt the growth of local capillaries.

Scientists aren't sure why cell shape should so adversely affect cell growth. Nonetheless, the discovery was important, since a drug which represses cell growth is precisely what you want to stem a tumor's growth.

Ingber, along with Folkman and their associates, sent the corrupted sample to Japan, where chemists grew the fungus in huge 10,000-liter vats in order to extract the potent compound. The Japanese found the active, capillary-suppressing agent to be the rare fungus fumagillin.

After working for years on finding such a drug, Ingber had uncovered a mother lode--but there was a catch. Fed to rats, large enough doses of fumagillin proved capable of suppressing tumors, but at the same time also caused severe weight loss.

A bit of chemical fiddling was enough to clear up the difficulty. Ingber and his colleagues synthesized from scratch in the laboratory an artificial likeness of fumagillin with all the tumor-suppressing capability, but without the side effects. The drug is known chemically as "AGM-1470."

Together, the Harvard researchers and their Japanese cohorts published their results in the December 6 issue of Nature. Only a couple of months old, the findings have already sparked the hopes of the entire industry of cancer researchers.

"That's real hot information," says Weidner. If such a drug turns out to be as effective as preliminary tests have indicated, he adds, "it would be really exciting."

From Research to Therapy?

Aside from the brief flashes of optimism, all parties involved in the research are quick to dampen unbounded enthusiasm. Thus far, the Harvard research has concentrated solely on breast cancer, a relatively "easy" type of tumor for clinical study.

Although breast cancer is of major scientific and clinical import--about 150,000 American women each year are afflicted with the disease--researchers are still in the dark about whether the same mechanism for tumor growth applies to all other cancers. Weidner's group is just now beginning to repeat the breast cancer research, by performing similar tests on prostate cancers.

And there are other hurdles. Before the federal government approves such drugs for treatment in humans, it requires an exhaustive series of tests to ensure against side effects. "We're just starting the bureaucratic process," Ingber says. "We hope to maybe get it into humans within the next year."

Folkman, for whom tumor repression would be a scientific coup of Nobel proportions, is likewise taking a long-term perspective. As for clinical usage of the drug, he says, "it's our goal, but it's not in sight yet."

Experts are quick to warn that cancer remains a leading killer of humans, and that the survival rate for metastasized tumors--cancers which have spread through the body--is still pitifully low.

Folkman likens the recent clinical success in combatting cancer to the nearly hopeless battle against pneumonia in the early years of this century, when the sometimes successful sulfa drug and later penicillin were introduced. Scientists then had little theoretical knowledge of pneumonia, but were nonetheless happy to have some kind of treatment, however flawed.

Today, clinicians are equally baffled by the mechanism by which an innocuous-looking tumor balloons up into a deadly cancer within the body. "Whether capillaries will grow or not grow toward a tumor may depend on one or more events that are not clearly understood at this time," the Harvard researchers wrote in the New England Journal paper.

But despite the obstacles that await them, the researchers remain optimistic about their work. As they conclude in their paper, "This information may prove useful even before we understand why it is true."