Dr Iain Brown, from the University of Aberdeen, Aberdeen, Scotland, told the conference that he and his colleague, Dr Andrew Schofield, had identified two genes that could identify which cells would be resistant and which would respond to docetaxel.
Docetaxel is one of the most effective chemotherapy treatments in advanced breast cancer. It works by binding to cell components called microtubules, and stabilising them so that they do not disassemble. They then accumulate within the cell and bring about apoptosis, or cell death. “However, up to half of all patients treated with this drug will develop resistance, and hence the treatment will fail,” said Dr Brown.
The scientists decided to look for a specific genetic make-up in patients where docetaxel treatment had failed, in the hope that this might explain why they became resistant to the drug. They used micro-array analysis, a technique that allowed them to look at every known gene in our cells at once, to identify genes that were significantly associated with such resistance.
“By going back to the laboratory, using breast cancer cell lines, we can eliminate much of the variation in gene expression found in different patients, and thus remove a lot of ‘background noise’,” said Dr Brown. “We developed a unique model of docetaxel resistance in breast cancer from two different cell lines made resistant to the drug by exposing them to increasing concentrations of the drug. This model has also allowed us to test cells which are resistant to low levels of the drug and cells which are resistant to high levels.”
Drs Brown and Schofield now intend to carry the research further, by applying their findings to patient samples to see whether the gene set they have discovered has the ability to predict response to docetaxel in a patient who has undergone treatment with the drug. “At the moment we have only tested this in cell lines,” said Dr Brown, “but we do believe these results may be translated into the clinical setting and benefit the patient. In essence, we have taken a clinical problem back to the laboratory, and now we intend to take this back to the bedside.”
The scientists will start collecting tissue samples from patients within the next six months. “If we find the same results in patient samples, we would expect that a simple test for docetaxel resistance could be developed and in clinical use within the next five years,” said Dr. Brown. Such a test would mean that those who would not benefit from docetaxel chemotherapy could be spared its side effects, and also reduce costs for healthcare providers.
“We think that the changes we have found may represent common drug resistance mechanisms in breast cancer cells,” said Dr Brown. “We are currently looking at these findings in other cancer types, especially those which are also treated with docetaxel, to see if the results may have a potential in other areas. This is the first time that the genetic pathways involved in the evolution of acquired resistance to docetaxel have been identified in a docetaxel resistant cell line model.”
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