Scientists at the University of California, San Francisco, have introduced a new class of drug - histone deacytalase inhibitors - meant to combat Tamoxifen resistance in patients with estrogen receptor-positive breast cancer tumors. Studies suggest that by taking both drugs together, one can reverse tamoxifen resistance. New insights into understanding Tamoxifen resistance in breast cancer patients have led scientists to look for ways that could potentially defeat this resistance.
The researchers discovered the molecular basis for Tamoxifen resistance and also evaluated means to overcome the resistance by administering a second class of drugs. The results of the clinical studies were presented by oncologist Pamela Munster and her colleagues, at the recently concluded AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics.
Understanding the mechanism of tamoxifen resistance and how to defeat it may help a large number of women with hormone-resistant breast cancer, said Munster, It may lead quickly to new, more effective treatment strategies and may help to identify biomarkers to help to gauge whether or not someone will respond to treatment in the first place.
The National Cancer Institute estimates that more than 200,000 Americans are diagnosed with breast cancer every year. It is the second leading cause of cancer death among American women and claimed more than 40,000 lives in 2009 alone. As per the new findings, scientists explained that epigenetics is a general phenomenon in biology that explains how some cells, tissues and whole organisms can acquire traits that go beyond mere genetic differences.
We always thought that resistance was genetic, said Munster, But now we have discovered that cells have a way of developing resistance by means of epigenetic modification.
About 65 percent of women with breast cancer have tumors. Related biopsies in these women show signs of choosing a naturally occurring molecule in the human body called the estrogen receptor. This receptor helps to stimulate the proliferation and growth of cells, something that is normally tightly controlled in the body. Tumors can use the mechanism of this receptor to stimulate the unregulated growth and proliferation of cancer cells itself.
Although tapped as a wonder drug, Tamoxifen does not work in some women because they may have forms of cancer in which the estrogen receptor does not actually play a central role. Also, by taking the drug many women also develop resistance to it.
In most cases, although the tumors respond to the treatment initially, the cancer has the potential to reoccur by proliferating even when the estrogen receptor is blocked.
The reason for this was blamed on genetics and scientists believed that certain variations in one's DNA passing from parents to children could be a factor for developing a tamoxifen-resistant form of breast cancer. But Munster negates this theory.
Rather than genetic mutations passing on to off springs, epigenetic changes are not in the genes themselves but in their levels of expression and activity.
According to the research, Munster and her colleagues explained that epigenetics accounts for Tamoxifen resistance. They discovered that when Tamoxifen targeted cancer cells, they sometimes responded by elevating expression of a gene known as AKT.
AKT is a survival gene that in normal situations helps to stimulate growth and proliferation of cells and prevents them from dying. In breast cancer, however, it can become overactive and pass on resistance by allowing the cancer cells to continue to use the estrogen receptor even in the presence of Tamoxifen, researchers explained.
Lead scientist Munster and her colleagues showed that when cells in the laboratory are fed histone deacytalase inhibitors, their levels of AKT are knocked back. However, if one were to feed them Tamoxifen, at the same time, it was possible to dramatically curtail the cell's ability to proliferate.
In clinical studies published earlier this year, Munster and her colleagues also showed that taking both drugs together can reverse tamoxifen resistance.
If proven in large-scale clinical trials, this new approach of treating breast cancer might prove to be safe and effective.