BioWorld International Correspondent

LONDON - A host of new insights into how the body fights ovarian cancer cells and how those cells evade natural control mechanisms is set to aid the application of forthcoming novel therapies.

Several new treatments for ovarian cancer are in the pipeline, all aimed at activating a pathway that can induce cancer cells to undergo apoptosis. Research by a team of scientists based in Austria now has explained two ways in which cancer cells become resistant to the cell-suicide pathway.

The study found that the pathway was impaired in more than 60 percent of ovarian tumors. Women in whose tumors the pathway remained intact had a much better chance of survival than those in which it was disrupted.

Michael Krainer, professor of medical oncology at the Medical University of Vienna in Austria told BioWorld International: "These findings are of great interest because they nail down an immunological mechanism that is important for the development of many cases of ovarian cancer - a mechanism that also is relevant for the prognosis of the disease, and for new therapies, which may be available on the market soon."

The work is reported in the Dec. 15, 2005, issue of Clinical Cancer Research in a paper titled "Perturbation of the TRAIL cascade in ovarian cancer: Overexpression of FLIP_L and deregulation of the functional TRAIL receptors DR4 and DR5." The first author is Peter Horak.

Concluding their paper, Horak and his colleagues wrote that their findings, coupled with those of others developing new therapies, make activation of the pathway "an exciting and auspicious candidate for ovarian cancer therapy."

The pathway concerned is known as the "TRAIL cascade." TRAIL stands for tumor necrosis factor-related apoptosis-inducing ligand. When that ligand, a protein, binds to its receptors, the cell enters a pathway that leads to apoptosis.

Tumor necrosis factor on its own also can trigger that process, but when it is given alone, it has highly toxic side effects. TRAIL, by contrast, has a desirably high therapeutic index, capable of preferentially killing tumor cells while leaving normal cells alone.

Several companies are developing recombinant TRAIL as a treatment for various cancers, while others are working on manufacturing antibodies that bind to the same receptors as TRAIL and thus also induce apoptosis.

Krainer and his colleagues have been exploring the role of the receptors for TRAIL in the biology of ovarian cancer for several years.

They already showed that when they combined TRAIL with classic chemotherapy agents, there was a strong synergistic effect on ovarian cancer cells grown in cell culture.

Secondly, they discovered that all the receptors for TRAIL that were necessary for the induction of apoptosis lay in the middle of a region of chromosome 8 that frequently is deleted in ovarian cancer cells.

Thirdly, they had demonstrated that ovarian cancer cells can become resistant to recombinant TRAIL by down-regulating one of the TRAIL receptors.

In their latest study, published in Clinical Cancer Research, they looked at the level of expression of TRAIL and two of its receptors in a panel of 68 ovarian cancer samples. They also measured the expression level of a protein called FLIP, which can inhibit apoptosis induced by TRAIL.

Krainer said, "We found that the TRAIL pathway was disrupted in more than 65 percent of cases, either by down-regulation of one of the TRAIL receptors, or by overexpression of FLIP."

They also determined that whether TRAIL was expressed in a tumor or not made a big prognostic difference. Patients with advanced cancer, with elevated expression of TRAIL in ovarian tissue, survived significantly longer than those whose ovaries did not produce high levels of TRAIL.

One of the team's most fascinating findings is that production of TRAIL took place in the cells around the tumor. Krainer said: "It looks as if fibroblasts in the microenvironment are producing TRAIL. They appear to be secreting it around the tumor cells. It is as though nature is doing something very similar to what scientists are planning with recombinant TRAIL - and, of course, the tumor cells often develop resistance to it."

Krainer and his team now are planning further investigations into the mechanism of resistance to TRAIL's effects.