By William J.
Successes so far with the much-ballyhooed, tumor-choking drug Endostatin are leading researchers to believe they can keep cancer patients alive for many more years with the help of nontoxic drugs that don't have the debilitating effects of large doses of chemotherapy and radiation. The hope is that such drugs will play a key part in holding cancer under long-term control just as medications keep diabetes, asthma, and other chronic diseases in check.
"Before the development of insulin, diabetes was as deadly as many cancers are today," says Joseph Paul Eder, who is testing Endostatin on patients with advanced cancers. "In a couple of decades, people may be able to live 30 to 40 years, or more, after being diagnosed with breast, prostate, or other cancers."
"Findings so far have shown that Endostatin has no serious side effects and that it stabilizes or even shrinks tumors," adds Donald Kufe, professor of medicine at Harvard Medical School. "With few if any side effects, this raises the possibility of keeping cancer under control for a lifetime."
Kufe, Eder and their colleagues at several Boston hospitals are treating patients with advanced cancer by giving them daily doses of Endostatin intravenously. Other patients are undergoing such treatments at M.D. Anderson Cancer Center in Houston and the University of Wisconsin Cancer Center. Although these tests are done to determine the safety, not the efficacy, of the drug, tumors stopped growing in some of the 61 patients who have been treated so far. One patient with deadly pancreatic cancer saw his tumor shrink by 20 percent. The huge jaw tumor of a patient in Texas shrank by 68 percent. Last week, researchers reported that a woman undergoing treatment in Boston since August experienced a tumor reduction of about 30 percent.
Kufe, Eder and other researchers recently began to give Endostatin continuously by means of a small, portable pump, attached to an intravenous needle, which patients wear all the time. A single dose of the drug given over 30 minutes injects high levels of it into the body, but these levels drop substantially before another dose is given 24 hours later. "The pump eliminates such peaks and troughs," Kufe notes.
Endostatin works by destroying small blood vessels that grow into the tumor and provide it with nourishment. Eliminating periodic troughs in delivery is expected to choke off any growth that restarts between the peaks. The pump also frees patients from a daily trip to the hospital.
"Several patients dropped out of the trials because the daily commitment of time was too exhausting," Eder notes. "A pump and refill lasts two days. That doesn't sound like much improvement, but it really is." Eder is an assistant professor of medicine at Harvard Medical School and treats patients at Dana-Farber Cancer Institute and Beth Israel Deaconess Medical Center in Boston.
Being able to take the drug in pill form would make life much easier for patients, so that's the next step. "At Dana-Farber, we developed an oral form of an Endostatin-type drug with colleagues in Japan," Kufe explains. Called NM3, it is already being tested on patients in France. Subject to approval by the Food and Drug Administration, researchers hope to start giving the pill soon to patients in the United States.
Another Endostatin-like drug called 2ME2 is being tested in pill form on humans at Indiana University Medical Center. So far, it has produced good results in breast cancer patients when used in combination with a chemotherapy drug, taxotere.
Such combinations were tried on animals at Dana-Farber as long ago as 10 years. A cocktail of Endostatin-like drugs used with low doses of chemotherapy "produced greater benefit than either alone," Kufe says. "That is particularly true for tumors that are resistant to drugs. Such drugs will also be useful with radiation, shrinking tumors with less toxic side effects than with radiation alone."
What triggers the growth of blood vessels in the first place remains unknown. Researchers believe tumors send out chemical signals that stimulate the genesis of these feeding tubes, a process known as angiogenesis. Endostatin and its relatives were shown to inhibit such growth by investigators working in the laboratory of Judah Folkman at Boston's Children's Hospital, just down the street from Dana-Farber.
"We suspect that some tumor types may have more than one way to stimulate angiogenesis," Kufe points out. "Endostatin may not completely block all these pathways, so a combination of angiogenesis inhibitors together with conventional chemotherapy drugs and with radiation may turn out to be the most effective treatment."
According to Eder, "There are now 10 to 15 different anti-angiogenesis drugs under test in humans. Some of these were developed specifically for suppressing blood vessel growth; others were found to possess this property while being studied for different purposes.
Thalidomide is one of the latter. Used by pregnant women in the early 1960s to ease morning sickness, the drug caused babies to be born with stunted arms and legs, no hips, or missing eyes. In the womb, fetuses require lots of blood vessels to properly develop their limbs, eyes, and other organs. Thalidomide, taken as a sedative, interfered with the growth of these vessels.
Today, its side effects are being put to work for inhibiting angiogenesis. At Dana-Farber and other locations, low doses of thalidomide show some promise for reducing bone marrow cancer (myeloma).
Ridding the body of unwanted blood vessels can be used to treat other diseases besides cancer. Their uncontrolled proliferation blinds people with diabetes (diabetic retinopathy) and causes loss of sight in elderly people (macular degeneration). Researchers at Folkman's lab are looking into the possibility of using thalidomide to treat such people.
"Much of the joint destruction in rheumatoid arthritis comes from scar tissue that's associated with abnormal blood vessel growth," says Eder. "Blocking that growth with Endostatin, or one of its relatives may help."
Endostation doses found to be most effective for cancers in ongoing tests will be given to patients intravenously, then to the same patients continuously by pump. That will allow the two methods to be compared. "We want to identify the best doses and the most effective way to deliver them," Kufe explains. "These Phase I trials should be completed by next May."
Phase I trials are devoted mainly to finding safe doses for patients. Promising finding of tumor shrinkage and stabilization have been a nice bonus. Phase II trials concentrate on how effective a drug is for treatment. Kufe and Eder hope to start Phase II trials of Endostatin by next summer.
"We'll concentrate on tumors where the drug appears to be most beneficial," says Kufe. So far that's been for pancreatic cancer, melanoma (an often lethal skin disease), and cancers of connective tissues like cartilage, bones and muscle.
"No effective drugs exist for these cancers," adds Eder. "Therefore, any kind of benefit we see will be significant."
There will also be tests of Endostatin together with other angiogenesis inhibitors and with conventional chemotherapy. "These are beginning as we speak," Eder notes.
"I think we're off a good start," Kufe sums up. "We have new drugs that show no toxic side effects. Once we learn how to use them properly and to combine them with other therapies that have proven useful over the years, we can look forward to keeping more people alive for longer periods and with fewer side effects."