Three-Drug Cocktail Shows Efficacy in Triple-Negative Breast Cancer

Doxorubicin, all-trans retinoic acid, and entinostat significantly reduced triple-negative breast cancer tumors in mice.

A triple-chemotherapy drug cocktail was found to shrink triple-negative breast cancer tumors, reported a study published in Cancer Research.

The triple cocktail includes doxorubicin, all-trans retinoic acid (ATRA), and entinostat. The cocktail is named EAD for each of its component drugs. ATRA has the ability to cause a tumor to lose its self-renewing cells, while entinostat makes cancer cells more sensitive to ATRA treatment.

Since retinoic acid drugs like ATRA can rid breast cancer cells of the ability to self-renew, multiply, and develop into more differentiated and mature breast cells, the tumor cells are less likely to grow and become invasive.

“If the cancer is supplied with agents that can cause their differentiation faster than their production, the tumor will shrink, since more cells are dying than are being produced to replace the dead ones,” said study co-author Vanessa Merino, PhD.

However, since retinoic acid drugs have limited success as tumor suppressors, researchers chose to combine ATRA with entinostat. The results of the study revealed that EAD significantly reduced triple-negative breast cancer tumors in mice, as well as the number of lab grown spheres of metastatic breast cancer cells harvested from patients.

After testing different drug combinations, the researchers determined that EAD was the most potent against the tumors. When doxorubicin was used alone, it reduced lab grown tumor spheres formation by 32%, while entinostat alone or ATRA alone was only able to reduce them by 18%.

When the drugs were combined, EAD therapy reduced sphere formation by 90%. Furthermore, EAD was able to reduce by 2-fold the number of tumor-starting cells in tumor spheres compared to the combination of entinostat and doxorubicin.

The findings suggest that ATRA can help move the tumor away from a “stem-like” state into a differentiated group of cells that are more responsive to drugs.

When evaluating the spheres grown from the metastatic triple-negative breast cancer cells of 6 patients, researchers found that EAD was most effective in decreasing tumor growth. The combination reduced the number of formed spheres by about 80%, compared with a 40% reduction in doxorubicin monotherapy.

The next step for the 3-drug cocktail is to evaluate the safety and efficacy in triple-negative breast cancer patients.