CURE FOR PROSTATE CANCERS? HUMAN TESTS TO START ON PROMISING NEW DRUG.

Byline: John Crewdson Chicago Tribune 

As physicians continue to sift applications in search of a half-dozen cancer patients qualified to join the first human tests of the prospective cancer drug endostatin, the latest research to emerge from the laboratory of endostatin's discoverer shows it can kill human prostate tumors in mice after only two six-week treatments.

The endostatin trial, set to begin later this month at the Dana-Farber Cancer Institute here, was initiated after endostatin virtually obliterated cancerous mouse tumors in a series of widely reported experiments in the laboratory of Dr. Judah Folkman at Boston's Children's Hospital.

Stunning as those results appeared, the tumors were mouse cancers artificially implanted on the skin of specially bred mice. Some researchers later suggested that endostatin might be less effective against ``orthotopic'' human tumors, which occur naturally inside the prostate, colon, lung and other organs, than in tumors on the surface of the head, neck or skin.

In the latest experiments, intended in part to address those criticisms, Folkman and his assistants grafted human prostate tumors onto the prostate glands of mice, then monitored the tumors' growth by measuring resulting levels of Prostate-Specific Antigen, which is a clinical marker for prostate cancer.

Following six weeks of treatment with endostatin, PSA levels in the mice dropped to zero, indicating the prostate tumors had shrunk to a microscopic dormant state. The treatments were stopped and the tumors allowed to regrow, then retreated until they once again reached dormancy. Although the tumors were expected to regrow for a third time, they never did.

``The PSA levels never came back up. That was somewhat of a surprise,'' said Dr. Michael O'Reilly, a Folkman associate who presented the prostate tumor data to a group of Harvard physicians and medical students at Beth-Israel Deaconess Medical Center recently. O'Reilly was informed before speaking that a Chicago Tribune reporter would be present.

After several months of continued dormancy, the mice were killed and their prostate glands dissected by two other Folkman assistants, Drs. Dipak Panigrahy and Wolfe Beecken, who designed the experiment. The prostate glands appeared pristine. ``They weren't able to find what they would call tumor,'' said O'Reilly, who discovered endostatin in Folkman's lab three years ago.

When O'Reilly previously conducted similar treat-and-retreat experiments with endostatin on skin-implanted mouse tumors, he found that four to six treatment cycles were necessary in most of the mice to achieve ``self-sustained dormancy'' in those tumors, compared with only two cycles in the prostate experiments.

``People think the orthotopic tumors are harder to treat. Actually, they might be easier,'' said Folkman, who now plans to try the same experiment in mice with other kinds of organ tumors before publishing the prostate data.

Still questions

Although the prostate tumors were of human origin, the fact they were reportedly cured in mice provides no clue to how endostatin will act in cancer patients with orthotopic tumors, who are expected to make up the bulk of the patients in the Dana-Farber endostatin trial.

Folkman and the Harvard researchers conducting the trial have emphasized repeatedly that results in mice frequently do not translate into comparable results in humans. ``If you're a mouse and you have cancer, we can take good care of you,'' Folkman says.

Those involved with the trial said that once the first group of apparently eligible patients for the endostatin trial had been randomly selected from among nearly 5,000 callers to a special Dana-Farber hotline, they would be invited to Boston for a series of clinical and laboratory tests to confirm their eligibility.

Because the trial is intended only to determine the maximum safe dose of that drug, researchers do not expect to see any improvement in the initial patients who will receive the lowest dose. Similar small groups of three to six patients will be added to the trial at higher dose levels throughout the fall.

O'Reilly's presentation of the prostate tumor remissions, the most significant endostatin results achieved thus far in mice, was followed by a report from scientists at EntreMed Inc., the Rockville, Md. company that manufactures endostatin under an agreement with Folkman's lab, that PSA itself might possess some of the same tumor-killing abilities.

Lung cancer 

The EntreMed research, published recently on an expedited basis by the Journal of the National Cancer Institute, found that treatments with PSA - which, like endostatin, attacks not tumors themselves but the cells from which new blood vessels are formed - reduced the progression of lung cancer in mice by 40 percent.

It is through preventing the generation of new vessels, a process called angiogenesis, that endostatin and other compounds, evidently including PSA, shrink tumors by cutting off their blood supply. Although the precise function of PSA has never been discovered, it now appears that PSA may form part of the body's defense against cancer.

``PSA's real functions have been in question for some time,'' said EntreMed president John W. Holaday. ``These findings confirm the earlier work of Dr. Folkman suggesting the body has its own ways of fighting disease as well as accelerating disease.''

The researchers at EntreMed, which is sponsoring the Dana-Farber endostatin trial, noted in their report that previous studies have detected PSA in patients with other kinds of cancer, including women with breast cancer, suggesting the PSA protein may not be prostate-specific after all.

In one such study of nearly 1,000 breast cancer patients, women who had higher levels of PSA had a better prognosis in terms of both recurrence and survival than women with lower levels, additional evidence PSA may possess some tumor-fighting qualities.

But Dr. William Catalona, a professor of urology at Washington University in St. Louis, cautioned there was some reason to believe the tests that appeared to detect PSA in nonprostate-cancer patients might have been measuring something else.

Understanding cancer

The latest Folkman and EntreMed findings also highlight, once again, the paradox of angiogenesis: If the body is capable of producing tumor-starving substances like PSA, endostatin and its companion protein angiostatin, another O'Reilly discovery, why does cancer occur at all?

The answer, according to Folkman and others involved in angiogenesis research, is that while those substances may suppress the growth of tumors in some, or even many, individuals, their natural levels are not sufficient to prevent tumor growth in patients who develop malignant cancers. The ultimate aim of the endostatin trial, and a separate angiostatin trial expected to begin early next year, is to see whether treating patients with either protein can tip the balance against the tumor.

Except for skin cancer, prostate cancer is the most commonly reported cancer

among men in this country, with an estimated 180,000 new cases and 40,000 deaths each year. Folkman notes, however, that autopsies find small, previously undiscovered prostate tumors in nearly half of men over 50 who die of other causes, suggesting that some natural force - perhaps an angiogenesis inhibitor - has held the tumors in check.

If PSA does act as a natural angiogenesis inhibitor, O'Reilly says, ``it would also make sense why so many prostate tumors are indolent,'' or slow-growing, compared with other more aggressive cancers.

But Catalona, whose work led to the widespread use of the PSA screening test as a diagnostic for prostate cancer, said it was equally possible the autopsied tumors were tiny simply because they were new and hadn't had time to grow to a detectable size.

In Folkman's latest experiments, increasing levels of PSA alone evidently were unable to stem the growth of the prostate tumors in mice without the assistance of endostatin. The explanation may lie in the finding by EntreMed researchers that PSA is between five and 10 times less powerful than endostatin or angiostatin.

In its published report, EntreMed suggested PSA, used as a drug, could ultimately become a treatment for cancer, and Holaday said the company has applied for a patent for that treatment. But Holaday said the company's current strategy is to focus on bringing endostatin and angiostatin to patients, mainly because those molecules are more potent than PSA.

While calling the EntreMed report an observation that deserves further study, Catalona also noted that the doses of PSA used to treat the mice in the EntreMed study were huge, 10,000 to 15,000 times higher than those in patients with the most advanced prostate cancers, and that if PSA were to be used as a therapeutic, massive infusions of the protein would be required.

Dr. George Wilding, a senior cancer researcher at the University of Wisconsin in Madison, emphasized that nothing in the current research diminished the value of PSA screening tests for the presence of prostate cancer and for monitoring the effectiveness of its treatment.

``PSA continues to have an important role in the diagnosis and treatment of prostate cancer,'' said Wilding, who will oversee another human endostatin trial expected to begin in Madison next month.

``I would encourage patients to continue to work with their doctors to monitor their PSA,'' Wilding said, ``and not misinterpret the results that a rising PSA is in fact indicative of something good, but still a sign of progression of their disease, or the presence of disease.''