In-development HDAC inhibitors could wipe out breast, ovarian cancer stem cells

Scientists at the University of Miami have developed a genetically engineered cell line to show that HDAC inhibitors could potentially target and stamp out “stubborn reservoirs” of breast and ovarian cancer stem cells.

Cancer stem cells often evade traditional cancer therapies that tend to target fast-growing cells. In addition to drug resistance, these stem cells are also associated with metastasis and relapse. They are hard to study because they divide slowly and are present in very small numbers, according to a statement. So, in order to isolate and understand these cells, the University of Miami team built an analog.

The team, led by Dr. Tan Ince, an associate professor at the university’s Miller School of Medicine, built a cell line mimicking cancer stem cells to test out drugs against certain HDACs--enzymes that control gene expression--that are overexpressed in breast and ovarian tumors. They used genetically engineered cells that share many traits of cancer stem cells, according to the statement.

The team compared their cell line mimicking cancer stem cells to one that emulated non-stem cancer cells and found that HDAC1 and 7 are overexpressed in cancer stem cells. They also found that these two HDACs are involved in preserving cancer stem cell levels in tumors as well, according to the statement. The researchers published their results in the journal Oncogene.

Seeking to identify potential inhibitors to combat these HDACs, they landed on two drugs that are currently in clinical trials for leukemia and lymphoma. These candidates targeted only HDAC1 and 7, which is important as more broadly targeted HDAC inhibitors can cause side effects, according to the statement.

"These two agents were designed to target HDAC1, but we found they also target HDAC7, which even the manufacturers didn't know,” Ince said in the statement. "This was perfect, like hitting two birds with one stone." The drugs slashed proteins associated with cancer stem cells and had durable effects: "We ran cell proliferation assays two to three weeks after treatment and could still observe the drugs' effects," Ince said.

HDACs have been targeted for a range of indications. Earlier this year, Sanford Burnham scientists found that a combination therapy involving the HDAC inhibitor panobinostat showed potential in treating mice with the childhood brain cancer medulloblastoma. And last October, Rutgers researchers used an HDAC inhibitor to preserve the ability to form new memories in rats with Alzheimer’s disease.