SAN FRANCISCO -- Researchers have shown how estrogen receptor-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 inhibitor in hormone therapy treatment can overcome resistance to hormonal therapy.
"We always thought that resistance was primarily an inborn or genetic effect," said Pamela N. Munster, M.D., director of the Early-Phase Clinical Trials Program at the University of California, San Francisco. "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 (HDAC) inhibitors."
Munster presented the findings at the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics, held Nov. 12-16, 2011.
She and her colleagues found that estrogen receptor (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 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.
This study was funded by the National Cancer Institute.
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The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, the AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes 33,000 laboratory, translational and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 90 other countries. The AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants, research fellowships and career development awards to young investigators, and it also funds cutting-edge research projects conducted by senior researchers. The AACR has numerous fruitful collaborations with organizations and foundations in the U.S. and abroad, and functions as the Scientific Partner of Stand Up To Cancer, a charitable initiative that supports groundbreaking research aimed at getting new cancer treatments to patients in an accelerated time frame. The AACR Annual Meeting attracts more than 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, treatment and patient care, and Educational Workshops are held for the training of young cancer investigators. The AACR publishes seven major peer-reviewed journals: Cancer Discovery; Cancer Research; Clinical Cancer Research; Cancer Epidemiology, Biomarkers & Prevention; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Prevention Research. In 2010, AACR journals received 20 percent of the total number of citations given to oncology journals. The AACR also publishes Cancer Today, a magazine for cancer patients, survivors and their caregivers, which provides practical knowledge and new hope for cancer survivors. A major goal of the AACR is to educate the general public and policymakers about the value of cancer research in improving public health, the vital importance of increases in sustained funding for cancer research and biomedical science, and the need for national policies that foster innovation and the acceleration of progress against the 200 diseases we call cancer.