BioWorld International Correspondent

LONDON - A new understanding of why some ovarian cancers are resistant to the commonly used drug, paclitaxel, could allow clinicians to channel treatment in future to those patients who will definitely benefit from it, and may lead to new therapies for this disease.

Scientists at the Cancer Research UK Cambridge Research Institute and the University of Cambridge have established that a protein found outside cancer cells determines whether they die when given paclitaxel.

James Brenton, Cancer Research UK group leader and honorary consultant in medical oncology at Addenbrooke's Hospital, Cambridge, told BioWorld International: "Paclitaxel is a standard treatment for ovarian cancer but about 50 percent of patients who receive it, and experience its unwanted side effects, do not benefit from it. This latest discovery may in the future allow us to individualize care for patients and ensure that they are receiving a drug that will help them."

It also may be possible to develop new drugs that could work even in the presence of resistance to paclitaxel, he predicted. "In the longer term, it may allow us to make this drug more useful for more patients," Brenton said.

Brenton and his colleagues reported their findings in the Dec. 10, 2007, issue of Cancer Cell, in a paper titled "The Extracellular Matrix Protein TGFBI Induces Microtubule Stabilization and Sensitizes Ovarian Cancers to Paclitaxel."

Microtubules are filamentous structures within the cell, made from subunits of tubulin proteins. Microtubules play an important role in cell division, particularly in helping to build the mitotic spindle. Cells that are undergoing division are constantly forming spindles and then, after division, breaking the spindle down into its constituent tubulin subunits.

Paclitaxel, a member of a family of drugs called taxanes, which were originally derived from the yew tree, work by binding to microtubules, and inhibiting the cell from breaking them up into their tubulin building blocks. Cells that become "stuck" in this way undergo apoptosis.

Previous research has shown that cancer cell lines that have become resistant to taxanes have acquired mutations in the genes encoding their tubulin proteins; often those types of mutation have the effect of changing the stability of the microtubules that form.

Brenton and his colleagues decided to investigate further the mechanism of resistance in cancer cell lines, and in tissue samples from patients with ovarian cancer.

"From looking at a cancer-cell-line model," Brenton said, "we discovered that a protein found in the extracellular matrix, called transforming growth factor beta induced, or TGFBI, was greatly repressed in cells that were resistant to paclitaxel."

When the team looked for evidence of this type of change in the tissue samples from about 20 patients with ovarian cancer, they found a correlation between low levels of messenger RNA for TGFBI and a clinically poor response to paclitaxel.

Further experiments showed that TGFBI is secreted by cancer cells into the extracellular matrix, where it binds to cell surface receptors called integrins. "We know that integrin can signal via the Rho and FAK pathways to stabilize the microtubules," Brenton said. "So if TGFBI is present outside the cell, it helps to stabilize the microtubules inside the cell."

The researchers have theorized that in the presence of high levels of TGFBI, microtubules are stabilized and present in relatively high proportions; when less TGFBI is present, there are fewer microtubules and more tubulin. In the latter case, there are fewer target molecules for paclitaxel to bind to, so the drug is less effective.

In all the cell lines that Brenton and his colleagues have looked at, resistance to paclitaxel has been induced by "knocking down" TGFBI using RNA interference.

Immunohistochemical staining of samples of ovarian cancer showed that where there was high expression of TGFBI, the tumor cells were dying; and vice versa.

When the researchers treated paclitaxel-resistant cells with recombinant TGFBI protein, the cells became sensitive to the drug once more, and died when it was added to the cultures.

The team now is going to examine tissue samples from several hundred patients with ovarian cancer, to determine how well TGFBI expression levels correlate with clinical response to paclitaxel.

"We want to know how often TGFBI expression is lost, and whether it can be used as a prognostic indicator," Brenton said.

In the longer term, the researchers want to probe what happens downstream of the integrin/Rho/FAK pathway. "I think it might be quite a challenge to find a therapeutic agent that would mimic the effect of TGFBI," Brenton said, "but if you knew which proteins downstream of Rho and FAK were altering the stability of the microtubules, these might be better drug targets. We are currently working on identifying these."

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