Abstract
Research on human breast cancer cell lines suggests that a combination of HDAC and PARP inhibitors with chemotherapy could be effective in treating triple-negative breast cancers that lack a BRCA1 mutation.
Many breast cancer therapies seem to bypass one group of patients—those with triple-negative breast cancer without the BRCA1 mutation. However, research on human breast cancer cell lines now suggests that a combination of HDAC and PARP inhibitors with chemotherapy could deliver the triple whammy that kills these aggressive cancers. The approach may also work in ovarian cancers that have similar genetic characteristics.
Triple-negative breast cancers do not respond to hormone-based therapies, but about 20% of these cancers have BRCA1 mutations or loss of function. BRCA1 is essential for a primary mechanism for repair of DNA damage to the cell. Without BRCA1, cells become genetically unstable and more vulnerable to the DNA-damaging agent cisplatin. A recent therapeutic strategy combines cisplatin with PARP (poly-ADP-ribose-polymerase) inhibitors, which interfere with another DNA damage repair mechanism. This approach, however, was not expected to work well in triple-negative breast cancers with functioning BRCA1, because these cancers retain the ability to repair DNA damage.
Researchers now report that they have given breast cancer cells with functioning BRCA1 the vulnerability of cells without it. Their research showed that inhibiting histone deacetylases (HDAC) effectively inhibits BRCA1, as well as ATR and CHK1, which also respond to DNA damage.
“HDAC inhibition gave these cells a ‘BRCAness’ that made them as sensitive to PARP inhibition and cisplatin as triple-negative cells with the BRCA1 mutation,” explained Kapil Bhalla, MD, a medical oncologist at the University of Kansas Cancer Center in Kansas City, who presented this work at the San Antonio Breast Cancer Symposium on December 6, 2012.
Working with pan-HDAC inhibitors either in clinical use (vorinostat) or clinical trials (panobinostat), Bhalla's group determined that each compound inactivated the heat shock protein HSP90, an important chaperone protein that keeps the DNA repair proteins folded in their active conformation.
Combining an HDAC inhibitor with the PARP inhibitor ABT888 (veliparib; Abbott) was more lethal to triple-negative breast cancer cells with or without BRCA1 mutations than either inhibitor was alone. Adding cisplatin to the mix was triple jeopardy, damaging DNA while deactivating several of the DNA repair mechanisms at once. The combined inhibitors selectively affect cells that need to repair DNA damage, and because the cisplatin damages the DNA of proliferating cancer cells more than normal cells, the inhibitors make the cancer cells more sensitive to cisplatin, said Bhalla.
Over the next several months, he and colleagues plan to test this triple combination against breast cancer stem cells and also to demonstrate the synergistic effect of the combination in mice. “These drugs are already in clinical research, and we know the safe levels,” Bhalla says. “We believe this is a rational combination for breast cancer patients who cannot use hormone therapies, and that our results are readily translatable.”