title: Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer.
abstract: BACKGROUND
  Metastatic thyroid cancers that are refractory to radioiodine (iodine-131) are associated with a poor prognosis. 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. Their effects in humans are not known.
  
  
  METHODS
  We conducted a study to determine whether the MAPK kinase (MEK) 1 and MEK2 inhibitor selumetinib (AZD6244, ARRY-142886) could reverse refractoriness to radioiodine in patients with metastatic thyroid cancer. After stimulation with thyrotropin alfa, dosimetry with iodine-124 positron-emission tomography (PET) was performed before and 4 weeks after treatment with selumetinib (75 mg twice daily). If the second iodine-124 PET study indicated that a dose of iodine-131 of 2000 cGy or more could be delivered to the metastatic lesion or lesions, therapeutic radioiodine was administered while the patient was receiving selumetinib.
  
  
  RESULTS
  Of 24 patients screened for the study, 20 could be evaluated. The median age was 61 years (range, 44 to 77), and 11 patients were men. Nine patients had tumors with BRAF mutations, and 5 patients had tumors with mutations of NRAS. Selumetinib increased the uptake of iodine-124 in 12 of the 20 patients (4 of 9 patients with BRAF mutations and 5 of 5 patients with NRAS mutations). Eight of these 12 patients reached the dosimetry threshold for radioiodine therapy, including all 5 patients with NRAS mutations. Of the 8 patients treated with radioiodine, 5 had confirmed partial responses and 3 had stable disease; all patients had decreases in serum thyroglobulin levels (mean reduction, 89%). No toxic effects of grade 3 or higher attributable by the investigators to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after radioiodine treatment, with progression to acute leukemia.
  
  
  CONCLUSIONS
  Selumetinib produces clinically meaningful increases in iodine uptake and retention in a subgroup of patients with thyroid cancer that is refractory to radioiodine; the effectiveness may be greater in patients with RAS-mutant disease. (Funded by the American Thyroid Association and others; ClinicalTrials.gov number, NCT00970359.).
authors: Head and Neck Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center and Weill Cornell Medical College, New York, NY 10065, USA.
authors: Alan L
authors: AL
authors: Ho
authors: Ravinder K
authors: RK
authors: Grewal
authors: Rebecca
authors: R
authors: Leboeuf
authors: Eric J
authors: EJ
authors: Sherman
authors: David G
authors: DG
authors: Pfister
authors: Desiree
authors: D
authors: Deandreis
authors: Keith S
authors: KS
authors: Pentlow
authors: Pat B
authors: PB
authors: Zanzonico
authors: Sofia
authors: S
authors: Haque
authors: Somali
authors: S
authors: Gavane
authors: Ronald A
authors: RA
authors: Ghossein
authors: Julio C
authors: JC
authors: Ricarte-Filho
authors: José M
authors: JM
authors: Domínguez
authors: Ronglai
authors: R
authors: Shen
authors: R Michael
authors: RM
authors: Tuttle
authors: Steve M
authors: SM
authors: Larson
authors: James A
authors: JA
authors: Fagin
mesh_terms: D000328:Adult; D000368:Aged; D001562:Benzimidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics / Q000627:therapeutic use*; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008297:Male; D008875:Middle Aged; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D064847:Multimodal Imaging; D009154:Mutation; D009362:Neoplasm Metastasis; D049268:Positron-Emission Tomography; D011874:Radiometry; D027981:Symporters / Q000187:drug effects / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000235:genetics / Q000473:pathology / Q000532:radiotherapy*; D057073:Thyrotropin Alfa / Q000494:pharmacology; D014057:Tomography, X-Ray Computed; D000099209:Sodium-Iodide Symporters
chemical_list: D001562:Benzimidazoles; D007457:Iodine Radioisotopes; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; D020928:Mitogen-Activated Protein Kinases; D027981:Symporters; D057073:Thyrotropin Alfa; D000099209:Sodium-Iodide Symporters; C517975:AZD 6244