Syndax reports promising results from entinostat preclinical studies in breast cancer

Syndax Pharmaceuticals, Inc., a clinical-stage epigenetics oncology company, announces results from two preclinical studies on entinostat, an orally bioavailable, highly selective, class I histone deacetylase (HDAC) inhibitor, in animal models of breast cancer. The data are being presented as oral poster discussions at the San Antonio Breast Cancer Symposium December 8 through December 12 in San Antonio Texas.

The following poster discussions are being presented:

• "A Combination of HDAC Inhibitor Entinostat (MS-275), All Trans Retinoic Acid (ATRA) and Chemotherapy Drug(s) Causes Regression of Established Xenografts of Triple Negative Breast Cancer" December 9, 2010 from 5:30 to 7:30 PM CT by Nguyen K. Nguyen from Johns Hopkins University School of Medicine
• "HDAC Inhibitor Entinostat Restores Responsiveness of Letrozole Resistant MCF-7Ca Xenografts to AIs through Modulation of Her-2" December 10, 2010 from 5:30 to 7:30 PM CT by Gauri J. Sabnis, Ph.D. from the University of Maryland School of Medicine

"These promising results in predictive animal models provide important insight into the molecular mechanisms by which entinostat can target resistance pathways in breast cancer," said Joanna Horobin, M.D., president and chief executive officer of Syndax. "In the phase 2 ENCORE 303 study presented at ASCO, we showed that the addition of entinostat could halt disease progression emerging on treatment with all of the commercially available aromatase inhibitors. Dr. Sabnis' work provides an elegant hypothesis supporting our clinical findings. We are optimistic that our ongoing ENCORE 301 study, a double-blind, randomized, placebo-controlled phase 2 study of entinostat in combination with the aromatase inhibitor exemestane, will provide further evidence supporting the clinical benefit and tolerability of entinostat in postmenopausal women with progressing metastatic breast cancer. We expect to see results in the first half of next year."

The University of Maryland study looked at the ability of entinostat to restore responsiveness of letrozole resistant MCF-7Ca xenografts to aromatase inhibitors. Entinostat was able to increase estrogen receptor expression and aromatase activity in the letrozole resistant tumors. The results suggest that entinostat may modulate Her-2 signaling and reverse the acquired resistance to letrozole caused by up-regulation of estrogen independent growth factor signaling pathways.

"While aromatase inhibitors have significantly improved the outcomes of hormone responsive post-menopausal breast cancer, not all tumors respond and many eventually acquire resistance," said Gauri J. Sabnis, Ph.D., assistant professor of pharmacology and experimental therapeutics at the University of Maryland School of Medicine. "These animal models have been confirmed in the clinic giving us hope that entinostat, if approved, will provide these women with a new treatment option to help overcome the resistance that many of them experience while on aromatase inhibitors."

Triple negative breast cancer (TNBC) is a sub-group of breast cancer that is normally unresponsive to hormone therapy as well as many forms of chemotherapy. Researchers from Johns Hopkins University School of Medicine reasoned that combining epigenetic therapy, entinostat, with differentiation therapy, retinoic acid receptor beta 2 agonist (ATRA) will provide an effective combination of drugs against TNBC. Low-doses of chemotherapy also were added to the combination. The results showed that entinostat plus ATRA and doxorubicin has the potential to be an effective treatment against TNBC.

"These findings provide encouraging new information for a non-toxic and novel combination of drugs with entinostat that could be effective in the treatment of triple negative breast cancer -- a condition desperately in need of new treatments," said Sara Sukumar, Ph.D., professor of oncology and pathology at Johns Hopkins University School of Medicine. "With chemotherapy as the primary treatment option for triple negative breast cancer patients, these results are encouraging that this patient population could have another treatment option in the future."