Molecular action of HDAC inhibitors improves chemotherapy in aggressive thyroid cancer

In their bid to find the best combination of therapies to treat anaplastic thyroid cancer (ATC), researchers demonstrated that all histone deacetylase (HDAC) inhibitors are not created equal. In testing multiple HDAC inhibitors in combination with the chemotherapy drug paclitaxel, known to give some benefit for this aggressive cancer, they found that class II HDAC inhibitors signal through a newly discovered pathway to promote synergy with chemotherapy treatment.

The study, published online in Endocrine Related Cancers (2015; doi:10.1530/ERC-14-0302), provided some surprising findings about HDAC inhibitors, which all seemingly do the same thing. They all remove the HDAC enzymes that wrap DNA so tightly that genes are silenced. There are 11 known HDACs. Blocking HDAC allows the genes to unwind, opening up like a toy spring to become active.

"Physicians and researchers should know that just using any of the many approved HDAC inhibitors for a patient's cancer may not offer the results one wants to see," said co-author Robert Smallridge, MD, an endocrinologist who treats thyroid cancer at the Jacksonville, Florida, campus of the Mayo Clinic. "That appears to be the case in ATC, and it is probably likely true in a number of cancers."

The Mayo team has long sought to understand ATC at a molecular level to find treatments that offer longer survival.

"Although ATC is rare, accounting for only 1% to 2% of thyroid cancers, it is responsible for up to 50% of thyroid cancer deaths," said senior author John Copland, PhD, a cancer biologist.

The mortality rate for ATC nears 100%. Diagnosis to death can be measured in weeks to months. When ATC is found early, it is treated aggressively, and patients can survive for a number of years.

"I doubt a single drug will ever work in this cancer, so it is a matter of finding which drugs in combination are going to be most effective," said Smallridge.

Even as he leads a national clinical trial testing a combination of paclitaxel chemotherapy with the experimental agent efatutazone, Smallridge is working with Copland and researcher Laura Marlow to find an HDAC inhibitor that might offer additional benefit.

HDAC inhibitors have been approved for use in blood cancers and are being tested for benefit in other cancers, such as breast, colorectal, gastric, liver, lung, and prostate cancers that overexpress specific HDAC proteins.

"HDAC inhibitors can increase activity of RhoB, a tumor suppressor that we had discovered earlier, that is switched off in ATC," said Copland. "We also know that this RhoB pathway, once turned on, can stimulate the expression of two proteins: p21, which prevents cells from replicating, and BIM, which induces cell death. Both of which can help stop cancer growth."

Marlow, the laboratory manager in Copland's lab, led the study by testing whether different HDAC drugs work with paclitaxel to turn on RhoB, and what effect they had on p21 and BIM.

"Only vorinostat and belinostat always induced the BIM protein, always induced cell death, and always showed synergy with paclitaxel," Marlow said.

That suggests that patient ATC biopsies should be examined before an HDAC inhibitor is used with chemotherapy to see whether p21 or BIM protein are being produced in the tumor during treatment, explained Smallridge. Thus, BIM upregulation and protein expression should predict a response to therapy and synergy of the two drugs, he says.

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