by Nancy Fliesler
The cancer-fighting drug endostatin, discovered in the Children's Hospital Boston laboratory of Judah Folkman, MD, has traveled a tortuous road. First reported in 1997, it showed tremendous promise in stabilizing and shrinking a variety of tumors.
But soon, a series of troubles began to knock the drug off course. By 2003, it seemed the end was near: endostatin's sole U.S. manufacturer announced that it would cease production, and clinical trials were cut short.
But recent developments—in Folkman's lab and in faraway China—have unexpectedly revived endostatin's prospects. Today, Folkman is cautiously optimistic that some form of his broad-spectrum, nontoxic agent will again be available to U.S. cancer patients. "The drug sort of wandered in the desert and came back out," he says.
Endostatin, a protein made naturally by the body, was first isolated by Michael O'Reilly, MD, in Folkman's lab. In 1997, papers in the journals Cell and Nature reported that it dramatically shrank tumors in mice through a unique mechanism: it starved tumors of their vital blood supply by blocking angiogenesis, or blood-vessel formation.
Unlike chemotherapy drugs, endostatin had no known toxicity because it was simply reproducing a substance that occurs naturally in the body. Nor did it induce drug resistance, another problem with chemotherapy, because it targeted blood vessels, whose cells are genetically stable and unlikely to mutate into a drug-resistant form.
On May 3, 1998, The New York Times trumpeted these discoveries on its front page, and media outlets around the world picked up the story. Oncologists were flooded with patient inquiries, and shares in EntreMed, Inc., endostatin's manufacturer, quadrupled in price. Folkman had tempered his enthusiasm, telling The New York Times, "If you have cancer and you are a mouse, we can take good care of you." But the intense publicity created unrealistic expectations for a drug still early in development, and a backlash ensued. "There was a lot of ridicule," Folkman says, "in the media and in science journals."
Despite the furor, Folkman and his colleagues kept working, sorting out the inevitable kinks involved in developing a new drug.
One challenge was figuring out how to manufacture endostatin. Folkman's lab was using genetically modified E. coli bacteria to produce the drug. "It was not very soluble, so it came out like toothpaste," Folkman recalls. "Purifying it was almost a useless task, because we had so little."
The insoluble paste worked just fine in mice. Injected under the skin, it produced a little white spot that disappeared over two to three days, and as reported in Cell, the animals' tumors shrunk. But scientists outside Children's complained that the paste didn't work, and that they couldn't replicate O'Reilly's findings. Trying to figure out why, Folkman got close colleagues to try using the paste, and finally Fed Exed some endostatin paste to himself. The problem was discovered: the endostatin was packed in dry ice, and the carbon dioxide was making it clump up.
That was easily fixed, but the paste form of endostatin was not deemed suitable for clinical trials. Instead, it had to be made by yeast. Unlike bacteria, yeast fold endostatin into the proper shape, making it soluble and crystal-clear. But the expense of maintaining yeast increased costs roughly tenfold.
Starting in late 1999, the yeast-manufactured endostatin moved into Phase I and II clinical trials; to date, it's been tested in about 160 cancer patients. The soluble formulation usually didn't shrink tumors, but it arrested them, and patients gained weight and got their strength back. Several patients with advanced cancers, for whom other therapies had failed, had long-term disease stabilization and greatly improved quality of life.
As Folkman's lab and others continued to study endostatin, it showed efficacy against a wide range of tumors—more than 30 at last count. Of all angiogenesis inhibitors made by the body, endostatin has the broadest anti-cancer spectrum, counteracting multiple angiogenic proteins secreted by tumors. And when given to mice with a tiny pump that released it continuously, endostatin did shrink tumors, just like the insoluble paste (which, the lab realized in retrospect, also provided continuous release).
But endostatin was being tested clinically as a twice-daily injection, not continuous release. Moreover, it was being judged against chemotherapy drugs, which made it look ineffective. Because chemotherapy is so toxic, and because surviving tumor cells can become drug-resistant and resume growing, anything less than 50 percent shrinkage of a tumor is reported as "no response," and stable disease is often considered a failure. In contrast, with endostatin, toxicity and drug resistance aren't concerns, so stable disease is a good result.
Nonetheless, the reports of "no response" with endostatin led to further bad press. This, coupled with the expense of making endostatin in yeast, led EntreMed to stop making the drug, and supplies began to dwindle.
That was very bad news for Nancy Hawkins, Ted Bielawski, Anita O'Brien and Scott Toner, the last four U.S. patients to receive endostatin. The drug had stabilized their disease to the point where, Folkman says, "The only way you could tell they had anything was on X-ray."
All four, treated at the Dana-Farber Cancer Institute, had to discontinue
endostatin last August when supplies ran out. Hawkins was switched to Avastin, an FDA-approved drug that blocks an angiogenic factor called VEGF, but her fatigue and weakness have returned. "I didn't feel like a cancer patient on endostatin," she says. "I do now."
The other patients have so far remained stable. Toner and Bielawski are also taking Avastin, but O'Brien is not. "Maybe the tumors forgot what they were supposed to do," she says. "But I'm waiting for the other shoe to drop."
Toner, diagnosed with a neuroendocrine tumor of the pancreas at age 31, assumed he would die and made no plans for his future. But on endostatin, his tumor stabilized. Five years later, he proudly passes out pictures of his newborn son.
Despite his stable disease, Toner doesn't want to take any chances. "Avastin's only protecting against one kind of angiogenic factor," he says. "I'd rather be back on endostatin."
Among those who took note of
endostatin's discovery was a young protein chemist named Yongzhang Luo, PhD. Born in China, he was doing a postdoctoral fellowship at Stanford University when endostatin broke onto the scene, and was impressed with endostatin's ability to regress tumors without toxicity or drug resistance. "That's like a dream," says Luo. He even bought EntreMed stock, but eventually lost most of his investment when the early endostatin bubble burst.
Intrigued by reports that other scientists had difficulty folding endostatin properly, Luo decided to work on the problem himself. "Since my postdoctoral training was on protein folding, I thought, 'Maybe we can solve the problem,'" he says.
In 1999, he returned to China, taking some U.S.-trained compatriots with him. His team solved the folding problem, adding nine amino acids to the endostatin molecule. This made it possible to manufacture a soluble endostatin using bacteria, not yeast, and at less expense. The reformulation was also more stable, more potent and lasted longer in the body, requiring just one injection daily rather than two.
With one-fifth of the world's new cancer cases, China is keenly interested in nontoxic therapies. Luo's corporate backer, Medgenn Ltd., has received millions of dollars in interest-free loans and grants from the Chinese government, and President Hu Jintao has visited the factory personally.
Clinical trials of the modified endostatin began in 2001 in patients with non-small-cell lung cancer, the leading form of lung cancer. Lung cancer rates are surging in China, with about 600,000 Chinese now dying of it annually. Evoking its benign toxicity profile, the drug was given the trade name Endostar, rendered in Chinese as "Endu," meaning "Graciousness."
Back in Boston, Folkman knew nothing of Endostar or even Luo's efforts. But in early 2005, he saw an abstract of a Phase III study to be presented at the annual American Society of Clinical Oncology meeting. The study involved 493 patients with advanced non-small-cell lung cancer, an impressively large sample, and found that Endostar, given together with chemotherapy, increased the average time to cancer progression from 3.6 to 6.3 months. Follow-up data, not part of the abstract, indicated a one-year survival rate of about 60 percent with Endostar, double that with chemotherapy alone.
The Chinese study wasn't slated for an oral presentation at the meeting and received little notice. But Folkman contacted Luo and learned that dozens of papers on endostatin had been published in Chinese journals. With the help of Chinese-speaking postdoctoral fellows in his lab, he had them all translated.
On September 12, 2005, the Chinese government approved Endostar for patients with non-small-cell lung cancer. Medgenn now hopes to extend clinical trials to other cancers, and is discussing marketing prospects with several U.S. pharmaceutical firms. Children's, which still holds patents, is likely to be involved in the negotiations.
Other developments are helping put endostatin back on the map. In more than 60 reports since 1997, endostatin-based gene therapy has significantly inhibited growth of primary tumors and their metastases. Recently, Oxford BioMedica in England licensed endostatin to develop a gene-based treatment called RetinoStat for patients with diabetic retinopathy and "wet" age-related macular degeneration, vision-threatening diseases caused by abnormal angiogenesis in the eye. The company aims to begin clinical trials this year or next.
And in Folkman's lab, biochemists Kashi Javaherian, PhD, and Robert Tjin Tham Sjin, PhD, researched endostatin's mechanism of action and found that a 27-amino-acid fragment of endostatin has all the anti-tumor activity of the full 183-amino-acid compound. This small peptide would be inexpensive to manufacture, and could be made synthetically, without the need for bacteria or yeast. Ronit Satchi-Fainaro, PhD, another biochemist in Folkman's lab, has modified the peptide to make it last longer in the body, which may allow it to be taken just once a week. Clinical trials are at least two years away.
Finally, other researchers have shown that certain oral drugs—like Celebrex, used to treat arthritis pain—increase blood levels of endostatin and other angiogenesis inhibitors. A few cancer patients have begun taking these drugs in hopes of preventing a recurrence.
In the meantime, Endostar's first U.S. customer may be Folkman himself: he is seeking FDA permission to import Endostar for Toner and the three endostatin patients. For all his frustrations, Folkman thinks endostatin's journey has been a fairly typical one for new drugs trying to move to the clinic. "I thought endostatin would never make it," he says. "It took some time, and it'll make it eventually. I hope we can get it soon because our patients need it."
To learn more about supporting Children's Hospital Boston's angiogenesis research, contact Joan Romanition, in the Children's Hospital Trust and Folkman Angiogenesis Research Institute, at (617) 355-2429 or joan.romanition@chtrust.org.
