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Kinase Inhibitor Reverses Radioiodine Resistance in Thyroid Cancer

Samson, Kurt

doi: 10.1097/01.COT.0000430995.72518.ea
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The kinase inhibitor selumetinib increased iodine uptake in 40 percent of advanced thyroid cancer patients whose metastatic disease was resistant to radioiodine enabling them to be treated, according to a study by researchers at Memorial Sloan-Kettering Cancer Center.

Patients who have metastatic thyroid cancer that is resistant to radioiodine have a 10-year survival rate of just 10 percent. Thyroid cancer incidence is growing rapidly, with a majority of cases being differentiated. Many patients with localized cancer can be successfully treated, but for those with metastatic cancer there are unfortunately few therapies.

Selumetinib is an experimental drug that inhibits MAPK kinase, which is activated by mutations of the oncogenes RAS or BRAF. In addition to treatment for thyroid cancer, selumetinib is also being studied as a potential treatment for non-small cell lung cancers, ovarian cancer, and melanoma.

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Figure

The new study, published in the New England Journal of Medicine ( 2013;368:623-632 ), found that selumetinib inhibited the genetic signaling of mutations in the MAPK pathway, especially in patients with thyroid cancers with a mutation in the NRAS gene.

A cell's ability to absorb radioiodine is inhibited when the MAPK pathway is inappropriately activated, explained lead author James A. Fagin, MD, Chief of the Endocrinology Service, adding that several earlier studies targeting other pathways have been unsuccessful in finding a way to overcome radioiodine resistance in patients with metastatic thyroid cancer.

In the study (first author is Alan L. Ho, MD, PhD), selumetinib, administered at 75 mg twice daily for four weeks, was given to 20 patients with radioiodine-resistant tumors, and after one month a diagnostic scan was performed to measure how much iodine-124 had been taken up by their tumors.

Twelve patients showed evidence of increased uptake, and eight reached a level that allowed them to be treated with radioiodine. Four out of nine patients with BRAF mutations and all five patients with NRAS mutations were in this latter group.

All five of these patients had major responses, and three had stable disease after treatment, the researchers reported. The reduction in metastatic tumor size was sustained in seven patients after six months, overall, but all patients showed markedly decreased levels of serum thyroglobulin, a protein marker of advanced thyroid cancer. Moreover, the patients experienced no serious side effects.

“By blocking this key pathway we were able to re-differentiate the tumors and allow them to re-acquire the ability to trap iodine so that radioiodine can potentially achieve its desired tumoricidal effect,” he said in an interview.

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Figure

“This is a novel approach, and a major advantage is that only a short course of drug therapy is required for a significant clinical effect. The initial results show promise for RAS-mutant disease, but the hope is that a larger trial will shed light on whether selumetinib can be effective for a broader range of advanced thyroid cancer subtypes,” he explained.

The researchers are now planning a placebo-controlled, multi-center phase III clinical trial in the United States and Europe. He said the study will hopefully be launched in the summer or early fall.

“This was a proof-of-concept study building on research in cells and in mice that showed that re-differentiating RAS and BRAF-mutant thyroid tumor cells by blocking MAPK signaling is possible. Hopefully the larger trial will shed light on whether selumetinib can be effective for a broader range of advanced thyroid cancer subtypes, treated at an earlier stage of the disease,” Fagin said.

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‘A Good Concept’

Asked for his opinion for this article, David Neil Hayes, MD, at the University of North Carolina School of Medicine's Lineberger Comprehensive Cancer Center, Chapel Hill, noted that thyroid cancer is a difficult disease to study in clinical trials due to the heterogeneity of patient populations in terms of the aggressiveness of the disease and the amount of prior therapy.

“The authors designed and executed an elegant study to evaluate this possibility,” he said. “Still, it would have been more reassuring to see a control arm in the study to increase confidence that the response rate to iodine in selumetinib-treated patients was greater than that seen in an untreated population.”

Hayes and colleagues recently conducted a multicenter trial to evaluate the efficacy, safety, and tolerability of selumetinib in patients with iodine-refractory papillary thyroid cancer (Clin Cancer Res 2012;18:2056–2065), and found that although selumetinib was well tolerated, the study was negative with regard to the primary outcome.

Figure. DAVID

Figure. DAVID

In 32 patients there was only one partial response after one year, although there appeared to be longer periods of disease stabilization for patients harboring activating mutations targeted by the drug, he noted.

“I see a lot of thyroid cancer patients, and most patients with papillary thyroid cancer are cured by a combination of surgery, radioiodine ablation, and long-term treatment, but patients with invasive or metastatic disease that fails to respond to radioiodine have few options. The opportunity to re-differentiate tumors and re-treat with iodine therapy would be a wonderful alternative for many patients.

“I think that it is a promising concept,” he continued. “I can imagine that re-differentiation of the tumors into a more iodine-sensitive indolent state might be associated with the more prolonged periods of disease stability we saw in our study.”

Because more than 70 percent of papillary thyroid cancers have mutations of RET/PTC, RAS, or B-RAF, and these effectors signal along the same pathway, pharmacological approaches to block MAP kinase signaling make sense, he noted.

“We do not know what the significant targets are, but we do know many have been described along this pathway and would be reasonable candidates. Unfortunately we don't know which are the ones that operate in vivo. Whether this is due to proliferation versus survival is unclear, but in the in vitro systems this is primarily a proliferation signal.”

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Larger Trial Welcomed

Another expert interviewed for this article, Bryan Haugen, MD, the Mary Rossick Kern and Jerome H. Kern Chair in Endocrine Neoplasm Research at the University of Colorado Anschutz Medical Campus, said there is a growing body of evidence that addressing MAPK mutations and signaling holds promise for resistant tumors.

Figure. B

Figure. B

“These results are very exciting. Each of these [mutations] could conceivably play a role in disease pathogenesis, which makes the choice of molecular target a difficult and critical decision,” he said.

Translational research has provided several advances in understanding thyroid cancer over the past decade, including the identification of RAS, and BRAF mutations, Haugen continued. As a prognostic genetic marker BRAF mutations have improved risk stratification and tailored treatment for many patients.

“Several drugs in this effort have failed, but this is a well-done study with very exacting results. By re-differentiating, this is a much less toxic therapy. Such treatments hold great promise for RAI cancers and are likely to become part of the standard treatment regimen in the near future. Hopefully the findings can be confirmed in a larger multi-institutional clinical trial.”

In his own research, Haugen, who last year received the American Thyroid Association's Paul Starr Award, studies the molecular mechanisms regulating thyroid function and neoplasms, including advanced thyroid cancer. Specific areas of research include nuclear hormone receptors (RXR, TR, PPAR) and kinase signaling pathways as therapeutic targets in thyroid cancer, as well as proteomic approaches to molecular markers in thyroid neoplasms.

© 2013 Lippincott Williams & Wilkins, Inc.
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