Entinostat for Breast Cancer

Annually about 207,000 women have breast cancer in the United States and about 20,000 of them have metastatic breast cancer (MBC). About 70 percent of women with breast cancer have estrogen receptor positive (ER+) breast cancer. Blocking estrogen activity with aromatase inhibitors represents an effective treatment for most ER+ MBC patients, however, acquired drug resistance to aromatase inhibitors leads to disease progression requiring less effective, more toxic chemotherapies8. Delaying resistance and disease progression represents a significant unmet need that could prolong survival while decreasing health care costs associated with chemotherapy and hospitalization.

Breast cancer animal models demonstrated that resistance to aromatase inhibitors occurs through up-regulation of growth factor signaling pathways and down-regulation of estrogen receptor-alpha (ER). Entinostat effectively down-regulates growth factor signaling in breast cancer cells where these pathways are active. Entinostat also up-regulates the expression of ER in breast cancer cells which have negligible or undetectable levels of ER. The ability to target multiple mechanisms of resistance establishes entinostat as a promising candidate for preventing and overcoming aromatase inhibitor resistance through epigenetic modulation. In a pre-clinical testing entinostat induced tumor regression when combined with an aromatase inhibitor after the development of hormone resistance.

ENCORE 303, a completed phase 2 multicenter, single-arm trial in metastatic ER+ breast cancer patients progressing on AI treatment, supported these preclinical results and demonstrated proof of principle. To confirm the results Syndax began a randomized phase 2 clinical trial, ENCORE 301, which was recently completed. The results will be presented later this year at a scientific conference.

Additional research is underway looking at entinostat in triple negative breast cancer through collaboration with the National Cancer Institute.