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HDAC Inhibitor May Overcome Resistance to Tamoxifen in ER+ Breast Cancer

Researchers have shown how estrogen receptor (ER)-positive breast cancer tumors become resistant to tamoxifen, the only approved hormonal therapy for premenopausal patients with this type of breast cancer. They also found that introducing a novel histone deacetylase (HDAC) inhibitor in hormone therapy treatment can overcome resistance to hormonal therapy. "We always thought that resistance was primarily an inborn or genetic effect," said Dr. Pamela N. Munster, director of the Early-Phase Clinical Trials Program at the University of California, San Francisco (UCSF). "But this is not the case. Tumors have found a way to modify their genes to become resistant. This process is called 'epigenetics,' where genes are turned on and off, but the sequence of DNA is not altered. We have also found that with this kind of breast cancer, we can prevent that resistance with histone deacetylase inhibitors." Dr. Munster presented the findings at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, held November 12-16, 2011 in San Francisco, California. She and her colleagues found that ER-positive breast cancer tumors alter their genes to create more AKT, a protein that spurs actions within the cell to keep it alive — the opposite of what tamoxifen is designed to do. In a preclinical study, researchers introduced the HDAC inhibitor PCI-24781 at an early phase of tamoxifen treatment and found that it reverses the tumor's survival strategy of increasing production of AKT, thus stopping the tumor cells from developing resistance and leading to higher levels of cell death. "The HDACs regulate the response of AKT to tamoxifen, and together, the effects of HDAC inhibitors and tamoxifen lead to more cell death if introduced with hormonal therapy," said Dr. Munster. She added that previous attempts to reverse hormone resistance were made later in the course of hormonal therapy treatment, "and we think that introducing these approaches earlier may be more successful," she said. The next step is to take this drug into clinical trials to investigate whether resistance to therapy can be prevented in patients with ER-positive breast cancer. A new look at AKT as a biomarker may help identify patients who are likely to benefit from this type of treatment. [AACR press release] [UCSF press release]