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Prof. Ziv Gil.(Photo by: MIKI KOREN/RAMBAM)
Israeli researchers decode thyroid cancer treatment resistance mechanism
The use of genetic engineering methods allowed researchers to express the PIGU protein in resistant cancer cells and lab animals and succeeded in restoring sensitivity to iodine therapy.
Researchers at Haifa’s Rambam Medical Center and Technion-Israel Institute of Technology have decoded for the first time the mechanism that leads some thyroid-cancer patients to be unaffected by treatment, providing hope for more successful therapies in the future.

Their research was recently published in the Journal of the [US] National Cancer Institute.

About 10% of people with thyroid cancer – one of the most common types of malignancies and more common in women than men – develop resistance to iodine therapy. In the absence of an effective therapeutic alternative, the survival rate of these patients is particularly low.

In Israel, as in the Western world, the incidence of thyroid tumors has doubled in the last 30 years, with this increase in prevalence mainly attributed to early diagnosis. At the same time, not only has there been no improvement in the mortality rate of patients with the disease, but death rates for those with advanced tumors have actually increased.

Researchers from Rambam and the Technion have discovered that the mechanism responsible for the resistance of thyroid tumors is connected to the treatment of iodine, which is the standard treatment for the disease. Treatment is based on partial or full surgical removal of the gland in the front part of the neck, supplemented by giving radioactive iodine if necessary. Thyroid cells are unique in that they transfer iodine through designated channels, allowing the radioactive iodine treatment to enter the cancerous cells scattered throughout the body and destroy them without harming other tissues in the body.

Although radioactive iodine is considered a standard treatment for thyroid cancer, some patients develop distant metastases or local recurrence that is resistant to iodine therapy. These patients have a dismal prognosis and low survival rates.

Although thyroid cancer treatment resistance has been known for decades, until now the cause has been unknown.

A multidisciplinary group of head and neck disease researchers in Haifa found the protein, named PIGU, which is responsible for transporting the iodine in the cells and anchoring them in the cell membrane. The researchers found significantly lower levels of this protein in cancer cells of patients whose tumors resist treatment than in those who responded well to the therapy. Patients with low levels of this protein required repeated treatments of iodine, without much benefit, while patients with normal protein expression responded well initially to the treatment.

The use of genetic engineering methods allowed researchers to express the PIGU protein in resistant cancer cells and lab animals and succeeded in restoring sensitivity to iodine therapy.

“This finding is of great importance to patients with resistance to iodine therapy, because new drugs that inhibit intracellular receptors can now be used,” said Prof. Ziv Gil, director of Rambam’s head and neck surgery department and head of the research group.

In addition, the discovery of the PIGU protein represents a promising marker for radioactive iodine response in patients with persistent thyroid cancer.

“There is no doubt that a better understanding of the mechanisms that regulate the transfer and anchoring of proteins in cancer cells will help physicians who are developing novel therapeutic strategies that may help in the survival of patients with thyroid tumors,” he said.
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