January 2006

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A cancer drug's star rises

The cancer-fighting drug endostatin, discovered in the Children's Hospital Boston laboratory of Judah Folkman, MD, has traveled a long and rocky road to clinical development. And only recently, it seemed that the end of the road was near: In 2003, endostatin's sole U.S. manufacturer, EntreMed, Inc., announced that it would stop making the drug, citing financial reasons, and clinical trials were cut short.

But two recent developments have unexpectedly changed endostatin's fortunes. On September 12, the Chinese government approved a modified version of endostatin for patients with non-small-cell lung cancer, after a Phase III trial in nearly 500 patients found that it delayed disease progression when added to chemotherapy.

And in May, Kashi Javaherian, PhD, and Robert Tjin Tham Sjin, PhD, from Folkman's Vascular Biology lab, reported that a small portion of the endostatin molecule—a peptide with 27 amino acids—has all the anti-tumor activity of the full compound, and is much easier and cheaper to manufacture.

Endostatin, a protein made naturally by the body, was first reported in 1997 to dramatically shrink tumors in mice by blocking angiogenesis, or blood-vessel formation, thereby starving tumors of their blood supply. In 1998, a front-page New York Times story touted this discovery and quoted Nobel Laureate James Watson as predicting that Folkman "will cure cancer within two years." Media outlets around the world picked up the story, and EntreMed"s stock surged in value.

The intense publicity created unrealistic expectations about endostatin, still early in development, and caused a backlash against the drug. Endostatin also proved expensive to manufacture, and with EntreMed's pullout from the market, production ceased in the U.S. And now, supplies in this country are virtually exhausted.

But in the meantime, endostatin was tested in about 160 cancer patients. In several patients with advanced cancers who had failed all other therapies, it has led to long-term disease stabilization and greatly improved quality of life.

In addition, unlike chemotherapy drugs, endostatin has virtually no toxicity, because it acts only on the endothelial cells that line blood vessels, without harming other cells. Nor do cancers become resistant to endostatin, a common problem with chemotherapy because endothelial cells divide slowly, making them unlikely to acquire mutations that confer resistance.

These qualities made endostatin attractive to the Chinese, who have one fifth of the world"s new cancer cases. Unbeknownst to Folkman and colleagues, a Chinese research team began studying endostatin soon after its discovery, forming a biopharmaceutical company, Medgenn Ltd., in 1999. Encouraged by the Chinese government, Medgenn modified endostatin to make it easier to manufacture and to last longer in the body, and began large-scale production. The modified drug, called Endostar, will now be tested against other cancers.

"The developments in China represent a very important advance," says Folkman. "Most of the angiogenesis inhibitors currently approved in the U.S., and in 28 other countries, block a single angiogenic factor produced by tumors, such as Avastin's blockage of vascular endothelial growth factor (VEGF). The Chinese have taken the next step, making available a broad-spectrum angiogenesis inhibitor that suppresses blood-vessel growth stimulated by many different types of angiogenic factors."

In the near term, Folkman is hoping to find a way to get Endostar to U.S. patients who were forced to go off endostatin when supplies ran out. But in the longer term, he believes the small peptide—which Children's is now pursuing for commercial development—could be a viable substitute for the original.

To read more, including a recent article in the Wall Street Journal, visit www.childrenshospital.org/research.

:: Anna Gonski, Editor :: Masthead ::

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