In two reports published in the Sept. 15 issue of the Journal of Clinical Oncology, the researchers say endostatin shows that it can decrease blood flow to some tumors in patients and promote death in cancer and blood vessel cells.
"There was a lot of enthusiasm for this drug, and while we are disappointed that we didn't see dramatic clinical activity, it's not surprising. For first generation drugs, progress is often incremental, but research should go on," says the studies' lead author, James Abbruzzese, M.D., professor and chairman of the Department of Gastrointestinal Medical Oncology at M. D. Anderson.
"Endostatin may well find a future place in the treatment of cancer, but that might be in combination with other therapies, and in less aggressive disease," says the studies' first author, Roy Herbst, M.D., Ph.D., associate professor of medicine in the Department of Thoracic/Head and Neck Medical Oncology.
Known publicly as endostatin and to scientists as recombinant human endostatin (rh-Endo), the agent was heralded in 1998 by the media and some scientists for its ability in animal research to dry up a tumor's source of blood, starving it. Human tests of this angiogenesis inhibitor were launched in 1999 at M. D. Anderson Cancer Center, the University of Wisconsin and Dana Farber Cancer Center.
In their report on the Phase I clinical trial of rh-Endo, M. D. Anderson researchers concluded the agent was both safe and well tolerated, even at different doses, by the 25 patients who received it. Patients stayed on the drug for a median period of 69 days. In two patients, there was evidence of minor anti-tumor activity -- several tumors were observed to shrink -- but no long-term responses were seen. All patients, who suffered from a variety of advanced cancers and had no other treatments available to them, died.
The researchers' other study describes the testing they undertook to see if rh-Endo was having any organic effect against cancer. This was an unusual and expensive analysis, but necessary to understand the action of this and other new biologic therapies, both now and in the future, says Abbruzzese.
The researchers used positron emission tomography (PET) to assess whether the agent was decreasing blood flow to tumors as well as disrupting metabolic activity within the tumors. They began PET measurements before therapy and at monthly intervals, and found that both blood flow and tumor activity generally decreased with increasing doses of rh-Endo. "But these effects were complex, not a straight relationship between dose and response," says Herbst.
To find out what was happening within the tumors, researchers took biopsies before the trial started and again at two months. Their results showed a significant increase in the death ("apoptosis") of cancer cells as well as in endothelial cells that form the lining of blood vessels leading to the tumor. Again, however, there was no relationship between dose of the drug and the destruction it caused, and may indicate that endostatin has a delayed onset of activity, says Herbst.
"This study is the first to suggest that endostatin can induce endothelial cell apoptosis and changes in tumor flow in some patients with advanced cancer," he says. "But in this trial we were treating established and aggressive tumors, and endostatin may work best as maintenance therapy in minimal disease, perhaps in combination with other agents, and at different dosing schedules.
"This study generates some questions and new hypotheses which must now be tested, but it also shows us that there is potential biologic activity against cancer that needs to be explored," Herbst added.
Both studies were supported in part by the United States Public Health Services, and the Houston-based Golfers Against Cancer. The Phase I study received additional funding from a Cancer Center Support grant, and the biomarker study was funded by an American Society of Clinical Oncology Career Development Award.