Exploring the Anticancer Potential of Valproic Acid in Advanced Thyroid Cancer
Name of the Trial
Phase II Trial of Valproic Acid in Patients with Advanced Thyroid Cancers of Follicular Cell Origin (NCI-10-C-0041). See the protocol summary.
Dr. Electron Kebebew, NCI Center for Cancer Research/p>
Why This Trial Is Important
Most thyroid cancers, especially when found early, are highly treatable and usually curable. About 90 percent of thyroid cancers are either of the papillary or the follicular type, both of which arise in the follicular cells of the thyroid. The cells of these tumors are usually well differentiated, meaning that they appear more similar to regular thyroid cells than cells of the rarer and more aggressive medullary and anaplastic types. Differentiated thyroid cancers are usually amenable to surgical resection and systemic therapy with radioactive iodine, which is readily taken up by the thyroid.
Patients with more advanced differentiated thyroid cancer may also be treated with radioactive iodine; however, some of these patients have tumors that fail to take up radioactive iodine adequately. External-beam radiation therapy and thyroid hormone suppression therapy may be alternative treatment options, but the long-term survival of these patients is low. Thus, it is important to identify better treatments for these patients.
A drug called valproic acid has been used for decades to treat people with mood or seizure disorders. Recently, researchers have begun studying this drug as a possible treatment for cancer. Valproic acid may act against cancer cells in a number of ways, and studies of the drug in tumor models support its clinical testing in people with cancer.
“Valproic acid has been in clinical use as a mood stabilizer and anticonvulsant for a very long time," said Dr. Kebebew. “Eventually, researchers discovered that it has other mechanisms of action, including as a histone deacetylase inhibitor, or HDAC inhibitor, which is a class of drugs known to have anticancer activity. When it was tested subsequently in the laboratory with cancer cell lines, valproic acid was found to inhibit the growth and invasiveness of thyroid cancer cells.
“These studies also revealed that the drug could affect the differentiation of cancer cells. This is very important in thyroid cancer because even metastatic sites of disease are quite effectively treated with radioactive iodine," Dr. Kebebew explained. “But that entirely depends on the thyroid cell being able to preferentially trap radioactive iodine. As thyroid cancer cells become dedifferentiated, they lose, or at least decrease expression of, a gene required for iodine uptake. So, the second effect of valproic acid in thyroid cancer is that it can actually increase the expression of this gene and allow the cancer to be treated with radioactive iodine."
In this trial, patients with advanced thyroid cancers of follicular cell origin whose tumors are not sensitive to radioactive iodine therapy will take valproic acid tablets for 10 weeks and then undergo a radioactive iodine uptake test. Patients whose tumors show increased uptake of radioactive iodine at 10 weeks will receive radioactive iodine therapy, whereas those whose tumors do not show increased iodine uptake will receive an additional 6 weeks of treatment with valproic acid. Doctors want to see if valproic acid will cause thyroid cancer cells to die, or at least stop growing, and if it will cause thyroid tumors to increase their uptake of radioactive iodine.