New Drug Prevents Spread of Ovarian Cancer

A drug that blocks production of an enzyme that enables ovarian cancer to gain a foothold in a new site can slow the spread of the disease and prolong survival in mice, according to a study, but only if the drug is given early in the disease process.

In the April 2008 issue of the Journal of Clinical Investigation, the researchers demonstrated that an enzyme known as MMP-2 is necessary for ovarian cancer to attach itself to the sites where it tends to spread. Several drugs known as matrix metalloproteinase (MMP) inhibitors (for example, marimastat or prinomastat) suppress the enzyme, drastically reducing the tumor's ability to establish itself at sites beyond the ovary. But such MMP inhibitors, abandoned after they failed to extend survival in earlier clinical trials, have to be given before the cancer has spread.

"Our study suggests that MMP-2 inhibitors could have a significant impact on ovarian cancer but only if administered quite early, before the cancer has advanced beyond the ovary,” said Dr. Ernst Lengyel, assistant professor of obstetrics and gynecology at the University of Chicago Medical Center (IL, USA).

This approach could help women who receive surgical treatment while the disease is still limited to the ovary as well as those who have successful surgery to remove all evidence of local spread of the disease. In the earlier trial, marimastat was given to women with late-stage disease that had already metastasized.

The fifth leading cause of cancer death in women, ovarian cancer--unlike breast, colon, or lung cancer--tends to spread within the abdominal cavity and not to distant organs. Carried by fluid, it most frequently spreads throughout the peritoneal cavity and to the omentum, a large fat pad draped over the small bowel.

Dr. Lengyel and colleagues tried to determine the many steps required for ovarian cancer to dislodge from its original site and establish itself elsewhere in the peritoneal cavity. They found that one of the key steps was production of MMP-2 by cancer cells that came in contact with the cells that line the peritoneal cavity.

When ovarian cancer cells make contact with the cells that line the peritoneal cavity, they produce MMP-2. MMP-2 alters two proteins--vitronectin and fibronectin--found on the surface of the cells that line the cavity. These alterations change those proteins in a way that enables the cancer cells to latch on to them better. Once attached, the cancer cells can multiply rapidly and invade.

By suppressing MMP-2 activity early in the disease course, the investigators were able to prevent injected ovarian cancer cells from attaching to their target tissues in the peritoneum and omentum. This reduced the growth of new tumors by 68%, when measured four weeks after treatment.

The inhibitor almost doubled survival time in mice that were injected with ovarian cancer cells. Those who received it survived an average of 63 days, compared to untreated mice, which survived only 36 days. Brief and early intraperitoneal treatment with an MMP inhibitor, the researchers concluded, may reduce peritoneal attachment, reduce metastases, and significantly prolong survival.

The treatment has much less impact, however, once cancerous cells have attached and formed colonies. In several earlier trials, marimastat, an oral MMP inhibitor, was given for a prolonged period to women with late-stage disease that had already spread.

"MMP-inhibitors were given at the wrong time for too long, causing side effects,” Dr. Lengyel said. Attachment is the first step for metastatic spread. MMP-2, the target of MMP inhibitors plays a role in early cancer spread. "Our study examines the initial step of ovarian cancer metastasis,” the researchers noted, when cancer cells meet unprepared target cells. Other steps in this process, they suggested, may also provide additional treatment targets.


Related Links:
University of Chicago Medical Center