Researchers have found that the investigational drug selumetinib shuts down the signaling of genetic mutations that prevent some patients’ thyroid cancer tumors from absorbing radioiodine, the most effective treatment for the disease.
Many patients with advanced thyroid cancer have tumors that are difficult to treat because they are unable to absorb radioactive iodine, or radioiodine, the most effective therapy for the disease. Recent findings from Memorial Sloan Kettering researchers, published in the February 14 issue of the New England Journal of Medicine, may indicate a new treatment strategy for these patients.
The phase II clinical trial found that selumetinib, an investigational drug that works by inhibiting a protein pathway called MAPK in tumor cells, reverses radioiodine resistance in some patients with advanced thyroid cancer.
“Blocking this key pathway increased the uptake of iodine, making radioiodine therapy potentially effective for patients who had a resistance,” says James A. Fagin, Chief of Memorial Sloan Kettering’s Endocrinology Service and senior author of the study. Dr. Fagin pioneered this research in cells and in mice.
Testing Selumetinib’s Potential
Therapeutic radioiodine is often given to patients with thyroid cancer after surgery to destroy any remaining cancer cells or thyroid tissue. Taken orally, usually only one or two doses of radioiodine are needed to treat a patient.
This therapy has been shown to increase survival in some patients with certain thyroid cancers that have spread to other parts of the body. Resistance to radioiodine can have an impact on a patient’s course of treatment.
Memorial Sloan Kettering researchers had previously demonstrated in cells and in mice that the MAPK pathway controls a cell’s ability to absorb radioiodine. As a result of this work, Dr. Fagin and his colleagues examined whether selumetinib, an MAPK pathway inhibitor, could reverse a patient’s resistance to radioiodine by inhibiting the signaling of particular genetic mutations in this pathway.
In the study, 20 patients with tumors resistant to radioiodine were given two doses of selumetinib every day for four weeks. To determine whether selumetinib reversed their tumors’ inability to retain radioiodine, researchers administered a form of iodine that, when absorbed, makes tumors visible on a PET scan. This diagnostic form of iodine has much less radiation than that of therapeutic radioiodine.
While most of the patients’ tumors were able to retain at least some of this diagnostic form of iodine, only eight patients absorbed a large enough amount to be eligible for radioiodine therapy. These eight patients, including all five of the patients with a mutation in a gene known as NRAS, were then given the therapeutic radioiodine.
During six months of follow-up, seven of the eight patients experienced either tumor shrinkage or a stop in tumor growth. All eight had a decreased level of serum thyroglobulin – a protein in the blood used to screen for advanced thyroid cancer – and none experienced serious side effects from selumetinib.Back to top
Determining the Benefit for Other Types of Advanced Thyroid Cancer
One advantage of selumetinib is that only a few weeks of therapy are required to improve a patient’s ability to absorb radioiodine.
“The initial results show promise for patients with a mutation in the RAS family of genes, particularly the NRAS gene, but the hope is that a larger clinical trial will shed light on whether selumetinib can be effective for people with other types of advanced thyroid cancer,” Dr. Fagin says.
Memorial Sloan Kettering will lead the international, multicenter phase III clinical trial of selumetinib, which will begin in mid-2013. The trial, which will be sponsored by AstraZeneca, will enroll patients who have recently had their thyroid gland removed – a procedure known as total thyroidectomy – due to thyroid cancer that has spread to nearby tissue or lymph nodes.Back to top