The Clinical-stage company Syndax Pharmaceuticals and the National Cancer Institute (NCI) will sponsor a multi-center Phase II study of entinostat, a novel inhibitor of histone deacetylases (HDAC), and anastrozole, an aromatase inhibitor, in postmenopausal women with operable triple negative breast cancer to evaluate biomarkers and surrogates for response.

Approximately 15-20% of all breast cancers do not express functional cell surface receptors like ER, PR, and HER2. Patients with triple negative breast cancer (TNBC) often have poorer prognosis compared to other breast cancer subtypes. It is commonly misconceived that TNBC is more sensitive to chemotherapy. Although higher pathologic complete response rate (pCR) was observed in TNBC (25?45%) compared to luminal breast cancers (6?7%), patients with TNBC had worse four-year distant disease-free and overall survival. [1]

A class I histone deacetylase inhibitor
Entinostat is an orally bioavailable, highly selective, class I histone deacetylase (HDAC) inhibitor with a long half-life that allows for weekly or every-other-week dosing. Entinostat is currently being investigated in multiple Phase II clinical studies including advanced breast cancer in combination with aromatase inhibitors, in combination with erlotinib in metastatic lung cancer and as a single agent in Hodgkin’s lymphoma.

Research has shown that HDACs are involved in the expression of various genes, such as the estrogen receptor, that regulate cell growth, differentiation and apoptosis. Such genes are frequently silenced in cancer cells through the over-expression of enzymes including HDACs. HDACs are therefore recognized as promising targets for cancer treatment. These studies have demonstrated that HDAC inhibition can significantly enhance anti-cancer activity when used in combination with a broad range of anti-cancer agents. The potential therefore exists to overcome tumor resistance to targeted agents.

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Trial in Triple Negative Breast Cancer
The trial, to be conducted under a Cooperative Research and Development Agreement (CRADA) executed between the NCI and Syndax, will investigate whether patient tumors can be reprogrammed to express estrogen receptor and render them to be sensitive to hormonal agents. This trial is based on animal data being published in the March 1, 2011, issue of Cancer Research.

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Laboratory studies by Dr. Angela Brodie, professor of pharmacology and experimental therapeutics, and Gauri J. Sabnis, Ph.D., assistant professor of pharmacology and experimental therapeutics at the University of Maryland School of Medicine, in collaboration with Saraswati Sukumar, M.S., Ph.D., professor of oncology and pathology at the Johns Hopkins University School of Medicine, provided the basis for the Phase II clinical trial. Their work demonstrates that entinostat induces hormone sensitivity in an animal model of triple negative breast cancer and that the combination with aromatase inhibitors prevents tumor growth as well as tumor metastasis.

“In the pre-clinical study that is being published in Cancer Research we demonstrated that entinostat can induce re-expression of estrogen receptor and aromatase in triple negative breast cancer cell lines and render them sensitive to an aromatase inhibitor,” said Saranya Chumsri, M.D., assistant professor of medicine at the University of Maryland School of Medicine and a medical oncologist at the University of Maryland Marlene and Stewart Greenebaum Cancer Center, principal investigator of the trial. “Moreover the combination of entinostat with an aromatase inhibitor suppressed the growth of tumors in an animal model of triple negative breast cancer. Given this promising data, we are evaluating entinostat with anastrozole in a neoadjuvant setting to see if we can extend the benefit of hormone therapy seen in patients with estrogen receptor positive breast cancer to those with triple negative disease – where cytotoxic therapy is the only treatment option.”

While the mortality rate in breast cancer has decreased in the past few decades, some subsets still have poor outlooks. With the advent of targeted therapy, particularly endocrine and anti-human epidermal growth factor receptor 2 (HER2) therapies, the outcome of breast cancer has changed dramatically. Nevertheless, approximately 15 – 20% of breast cancers lack expression of all three constructive cell surface receptors, namely estrogen receptor (ER), progesterone receptor (PR) and HER2, hence the term “triple negative” breast cancer (TNBC). Due to an absence of ER and/or PR, these tumors typically do not respond to endocrine therapy like tamoxifen and aromatase inhibitors, which have minimal toxicities and are generally well tolerated. For that reason, the treatment option for these tumors is solely chemotherapy.

It has been demonstrated in multiple studies that the loss of ER protein expression is a result of epigenetic changes such as aberrant DNA methylation and recruitment of histone modifying enzymes to the ER promoter in the tumors. Targeting such changes with epigenetic treatments has been validated as a successful strategy in other cancer indications and the data being published suggest that it may be effective as a therapeutic intervention in the treatment of ER-negative breast cancers.

“Triple negative breast cancer is a particularly challenging form of breast cancer that is normally unresponsive to hormone therapy as well as many forms of chemotherapy,” said Joanna Horobin, M.D., president and chief executive officer of Syndax. “The pre-clinical research provides us with a provocative question. Can we turn some of these tumors into estrogen receptor positive breast cancer and extend the benefit of well tolerated hormone therapy to this otherwise underserved patient population? The clinical study is designed to address this issue.”

This multi-center trial sponsored by NCI is being coordinated through the University of Chicago Consortium.

Fore more information:
WJ I, LA C. What is triple-negative breast cancer? Eur J Cancer:doi:10.1016/j.ejca.2008.09.034, 2008

Clinical trials:
Entinostat and Anastrozole in Treating Postmenopausal Women With Triple-Negative Breast Cancer That Can Be Removed by Surgery.

Reference:
Sabnis GJ, Goloubeva O, Chumsri S, Nguyen N, Sukumar S, Brodie AMH. Functional Activation of the Estrogen Receptor-? and Aromatase by the HDAC Inhibitor Entinostat Sensitizes ER-Negative Tumors to Letrozole. Published OnlineFirst January 18, 2011; doi: 10.1158/0008-5472.CAN-10-2458 Cancer Res March 1, 2011 71; 1893.

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