Mayo researchers decode molecular action of combination therapy for deadly thyroid cancer

In their bid to find the best combination of therapies to treat anaplastic thyroid cancer (ATC), researchers on Mayo Clinic's Florida campus 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.

They say their study, published online today in Endocrine Related Cancers, provides some surprising findings about HDAC inhibitors, which all seemingly do the same thing -- 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 Slinky 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," says co-author Robert Smallridge, M.D., an endocrinologist who treats thyroid cancer. "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 1-2 percent of thyroid cancers, it is responsible for up to 50 percent of thyroid cancer deaths," says John Copland, Ph.D., a cancer biologist and the study's senior author.

The mortality rate for ATC nears 100 percent. 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," says Dr. Smallridge.

Even as he leads a national clinical trial testing a combination of paclitaxel chemotherapy with an experimental agent known as efatutazone, Dr. Smallridge is working with Dr. 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," says Dr. 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."