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Selumetinib increased radioiodine uptake in thyroid cancer
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The MEK inhibitor selumetinib boosted uptake and retention of radioiodine in patients with refractory thyroid cancer, according to data published in The New England Journal of Medicine.
“In mouse models of thyroid cancer, selective mitogen-activated protein kinase (MAPK) pathway antagonists increase the expression of the sodium–iodide symporter and uptake of iodine,” the researchers wrote. “We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer.”
Alan L. Ho
After adhering to a low-iodine diet for 5 days followed by a thyrotropin alfa-stimulated iodine-124 (I-124) PET-CT study and then twice-daily treatment with selumetinib 75 mg for 4 weeks, patients underwent a second iodine-24 PET study to determine whether iodine uptake in the lesion or lesions was increased. If a patient experienced increased iodine uptake, the researchers estimated the dose of radioiodine (I-131) required to deliver a projected absorbed dose of at least 2,000 cGy to the lesion and administered radioiodine therapy while also continuing treatment with selumetinib.
Twenty of 24 patients (median age, 61 years) with differentiated thyroid carcinoma of follicular-cell origin or its respective variants were available for evaluation — nine of whom had tumors with BRAF mutations and five of whom had tumors with NRAS mutations. The researchers found increased I-124 uptake in 12 patients — four with BRAF mutations and five with NRAS mutations. Eight of these 12 met the threshold for treatment with I-131, according to the researchers, including all five with NRAS mutations. Five of these eight patients had partial responses and three had stable disease, and all patients experienced a mean reduction of 89% in serum thyroglobulin levels. The researchers determined that selumetinib was not responsible for any toxic effects of grade 3 or higher. One patient, however, was diagnosed with myelodysplastic syndrome, with eventual progression to leukemia, more than 51 weeks after treatment with I-131.
“These results provide a proof of principle that MEK inhibitors can induce iodine uptake and retention in thyroid tumors,” the researchers wrote. “An advantage of this therapeutic strategy over long-term treatment with small-molecule kinase inhibitors alone is that only a short course of drug therapy is required to elicit a durable clinical effect.”
Disclosure: This study was supported by grants from the American Thyroid Association, the Society of Memorial Sloan-Kettering Cancer Center, the NIH, AstraZeneca and Genzyme. The I-124 PET studies were supported in part by a grant from the In-Vivo Cellular and Molecular Imaging Center.
Perspective
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Richard J. Robbins, MD, FACP
The Thyroid Cancer group at Memorial Sloan-Kettering Cancer Center has made an important new observation. Annually in the US, there are an estimated 1,850 deaths from thyroid carcinoma. More than 70% of the oncogenic mutations in papillary thyroid carcinoma result in over-activity of the MAP kinase pathway, which stimulates proliferation and inhibits the sodium-iodide symporter (NIS). The loss of NIS not only makes radioiodine less effective, it is a hallmark of a biological shift of the cancer cells to a more aggressive phenotype.
For more than 15 years, the Memorial Sloan-Kettering team and many others have been searching for the “Holy Grail” of an agent that could re-differentiate metastatic thyroid cancer cells into trapping enough I-131 to deliver clinically meaningful radiation. There have been a handful of individual case reports in which one biological agent or another may have increased the radioiodine avidity of a metastatic lesion. This publication is the first well-documented example that re-expression of iodine trapping can translate into improved clinical outcomes for a cohort of patients. One key element that enabled them to quantify this effect is a positron emitting isotope of iodine, I-124. The ability to quantitate I-124 within a specific lesion and predict the radiation that it might receive (i.e. lesion dosimetry) following a therapeutic dose of I-131 is a brilliant technical achievement. The hope is that this seminal observation will encourage other teams to investigate similar agents that abrogate oncogenic signaling pathways which, like MAP kinase, are known to be overly expressed in advanced thyroid carcinoma.
Perspective
Back to TopSteven I. Sherman, MD
The study by Ho and colleagues introduces a novel approach to trying to augment the effectiveness of radioiodine therapy for differentiated thyroid cancer. If validated in larger, multicenter cohorts, this therapeutic strategy could expand the use of radioiodine to treat metastatic disease as well as potentially provide a way to enhance the effectiveness of adjuvant radioiodine therapy in the absence of known metastatic disease. Caution would need to be applied, however, to ensure that this does not encourage more widespread use of radioiodine when it is truly ineffective or unnecessary, as significant long-term toxicities remain of major concern.
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