A Cancer Drug’s Star Rises – An Endostatin Update, Nov. 2005
http://www.childrenshospital.org/research/Site2029/mainpageS2029P27sublevel30.html
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
government of China 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 antitumor activity of the full compound, with the benefit of being much easier and
cheaper to manufacture.
Crystal structure of endostatin.
The area shaded in orange
represents endostatin's hP1
peptide -- the section of
endostatin that has the antitumor
properties of the full compound.
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. Supplies in this country are now 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
biopharmaceutal 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.
http://www.biooncology.com/bioonc/approach/antiAngiogenesis.m?s_cid=0003&s_src=googleppc
Tumor angiogenesis represents a continuous and important process in tumor development in which the
tumor attempts to gain an independent blood supply. This process is driven by the tumor's release of proangiogenic signals, such as VEGF, which bind to receptors on nearby blood vessel endothelial cells.
VEGF has been identified as the most potent of the pro-angiogenic factors. Other factors also play an
important role in the growth and stabilization of new vessels, including vascular endothelial migration
factor (VEMF), platelet-derived growth factor (PDGF), and a vascular growth factor produced by certain
glands (EG-VEGF).
http://psa-rising.com/medicalpike/angiostatinduke399.htm The field of angiostatin research grew from the
observation that some, but not all, tumors seem to be able to control the spread, or metastasis, of cancer
elsewhere in the body. Cancer physicians have long known that sometimes, when a single large tumor is
removed from a patient, subsequent tumors will come back quickly and spread, seeding the body with
deadly fast-growing tumors.
Folkman proposed about ten years ago that tumors themselves regulate the growth of blood vessels.
One notion was that tumors could produce proteins that would travel through the bloodstream, preventing
vessels from growing to any new cancer metastasis. This idea explains what has been observed, although
no one understands why a tumor would exert such control, or why only some tumors work in this way.
Folkman's lab later found the substance that inhibits blood vessel growth. It was a small piece of a large
and common blood protein called plasminogen, which is involved in blood clotting. He called this protein
"angiostatin," and demonstrated it was involved in "anti-angiogenesis" -- stopping the process of new
blood vessel growth.
Other Resources:
http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/A/Angiogenesis.html
NY Times March 18, 2008
Second Opinion: A Daring Treatment, a Little Girl’s Survival
By DENISE GRADY
In the pages of a medical journal, Melanie Joy McDaniel is a study subject, listed by her patient number
and tumor type. In real life she’s a little girl whose story is a reminder that medical research can change
lives and that the pioneers include patients, some of whom are babies. Melanie was 9 months old when
her parents faced an agonizing decision. She had already had two operations for a malignant brain tumor,
and doctors could not be sure they had removed all the cancer. She needed more treatment, but standard
chemotherapy offered little hope in exchange for its harsh side effects. And yet the McDaniels knew that
if they did nothing, the odds were high that the tumor would come back.
Doctors at the Dana-Farber Cancer Institute in Boston offered another option, an experimental treatment.
To qualify, a child had to have a progressive cancer, and it had to be terminal. The McDaniels took a
gamble and a leap of faith, and signed Melanie up. “It won’t save her, but it may help other people,” her
father, Paul McDaniel, told me in an interview for a Science Times article published in April 2002. Then
he paused and added, “Maybe it will save her.” By then, Melanie had been receiving the test therapy for
five months, and her brain tumor, a type called an ependymoma, had not grown. That was encouraging,
but the treatment still seemed like a long shot. After the article was published, I was afraid to call the
McDaniels again. I didn’t think Melanie would survive.
Recently, Mr. McDaniel sent me an e-mail message. “Melanie is now 7 years old, attending first grade,
and doing very well,” he wrote. “The doctors told us last year that they do not see any residual tumor in
her brain. Their original diagnosis was that her tumor had no known cure.” What had prompted him to get
in touch was the death on Jan. 14 of Dr. Judah Folkman, the researcher at Dana-Farber whose work had
led to Melanie’s treatment. Mr. McDaniel wrote that he wanted “to celebrate the accomplishments of Dr.
Folkman, who faced resistance on his ideas that, by the grace of God, cured my daughter of an incurable
brain tumor.” Dr. Folkman founded a branch of research based on the theory that tumors need a blood
supply in order to grow and can stimulate the formation of new blood vessels — angiogenesis — to feed
themselves. If angiogenesis could be stopped, he reasoned, it might be possible to starve tumors. His work
ultimately led to useful treatments but took years to gain acceptance in a field that was focused on
attacking cancer cells directly.
Melanie McDaniel became one of 20 children with advanced cancer who were enrolled in a study that
used drugs strictly to fight angiogenesis. The drugs included two standard anticancer medicines, but in
small doses meant to stop blood vessels from forming, not the much bigger amounts needed to poison
tumor cells. The children also took two other drugs that had been found to block angiogenesis. One was
Celebrex, usually given for pain and inflammation. The other was thalidomide, notorious for causing
stunted limbs and other birth defects when pregnant women took it in the 1960s — damage, it was later
learned, that the drug inflicted by halting the growth of blood vessels in the fetus. Melanie and the other
children were given small doses of medicine by mouth every day, instead of big doses intravenously
every few weeks. The idea was that continuous treatment might keep blood vessel growth in check,
whereas the usual schedule of therapy every few weeks could give new vessels a chance to sprout
between doses. Doctors also hoped that the small doses would minimize side effects. The approach is
called metronomic, low-dose or antiangiogenic chemotherapy.