An emerging role for proteostasis modulators targeting NIS activity to enhance radioiodide therapy in thyroid cancer

Pulmonary metastases were found in 123 out of 840 patients with thyroid cancer between 1955-1977. 87 patients with pulmonary metastases of differentiated cancer were studied in detail, including an evaluation of prognostically important factors. In 66 of them, the induction of 131I uptake in metastases was attempted, in half of them successfully. Uptake was achieved more frequently in younger subjects, in papillary cancers and in patients with fine pulmonary metastases on chest films. Survival (not corrected for age) was evaluated 10 and 15 years following the diagnosis of thyroid cancer and was found to be 29,1 % and 12,2%, respectively. Significantly higher survival rates were seen in younger patients, in patients with the fine type of pulmonary metastases, in the absence of bone metastases and, particularly, in patients with induced 131I uptake in metastases. Papillary cancers were found to have higher survival rates in males and in young subjects only, in the whole group the survival rates were independent of either microscopic type or sex. It is believed that biologic behaviour of distant (pulmonary) metastases may be influenced by radioiodide therapy.

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Faculty Opinions recommendation of CD133-expressing thyroid cancer cells are undifferentiated, radioresistant and survive radioiodide therapy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717961263.793466555 ◽

2012 ◽

Author(s):

Gilbert Cote

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Radioiodide Therapy ◽

Thyroid Cancer Cells

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Image-Guided Radioiodide Therapy of Medullary Thyroid Cancer After Carcinoembryonic Antigen Promoter-Targeted Sodium Iodide Symporter Gene Expression

Human Gene Therapy ◽

10.1089/hum.2007.081 ◽

2007 ◽

Vol 18 (10) ◽

pp. 916-924 ◽

Cited By ~ 49

Author(s):

Christine Spitzweg ◽

Claire H. Baker ◽

Elizabeth R. Bergert ◽

M.K. O'Connor ◽

John C. Morris

Keyword(s):

Gene Expression ◽

Thyroid Cancer ◽

Carcinoembryonic Antigen ◽

Sodium Iodide ◽

Medullary Thyroid Cancer ◽

Sodium Iodide Symporter ◽

Medullary Thyroid ◽

Image Guided ◽

Radioiodide Therapy

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Molecular Analysis of the Sodium/Iodide Symporter: Impact on Thyroid and Extrathyroid Pathophysiology

Physiological Reviews ◽

10.1152/physrev.2000.80.3.1083 ◽

2000 ◽

Vol 80 (3) ◽

pp. 1083-1105 ◽

Cited By ~ 207

Author(s):

Antonio De la Vieja ◽

Orsolya Dohan ◽

Orlie Levy ◽

Nancy Carrasco

Keyword(s):

Thyroid Cancer ◽

Molecular Analysis ◽

Posttranslational Modifications ◽

Wide Spectrum ◽

Sodium Iodide Symporter ◽

Iodide Transport ◽

Thyroid Hormone Biosynthesis ◽

Lactating Mammary Gland ◽

Transport Defect ◽

Radioiodide Therapy

The Na+/I−symporter (NIS) is an intrinsic membrane protein that mediates the active transport of iodide into the thyroid and other tissues, such as salivary glands, gastric mucosa, and lactating mammary gland. NIS plays key roles in thyroid pathophysiology as the route by which iodide reaches the gland for thyroid hormone biosynthesis and as a means for diagnostic scintigraphic imaging and for radioiodide therapy in hyperthyroidism and thyroid cancer. The molecular characterization of NIS started with the 1996 isolation of a cDNA encoding rat NIS and has since continued at a rapid pace. Anti-NIS antibodies have been prepared and used to study NIS topology and its secondary structure. The biogenesis and posttranslational modifications of NIS have been examined, a thorough electrophysiological analysis of NIS has been conducted, the cDNA encoding human NIS (hNIS) has been isolated, the genomic organization of hNIS has been elucidated, the regulation of NIS by thyrotropin and I− has been analyzed, the regulation of NIS transcription has been studied, spontaneous NIS mutations have been identified as causes of congenital iodide transport defect resulting in hypothyroidism, the roles of NIS in thyroid cancer and thyroid autoimmune disease have been examined, and the expression and regulation of NIS in extrathyroidal tissues have been investigated. In gene therapy experiments, the rat NIS gene has been transduced into various types of human cells, which then exhibited active iodide transport and became susceptible to destruction with radioiodide. The continued molecular analysis of NIS clearly holds the potential of an even greater impact on a wide spectrum of fields, ranging from structure/function of transport proteins to the diagnosis and treatment of cancer, both in the thyroid and beyond.

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Innovative strategies for the treatment of thyroid cancer

Acta Endocrinologica ◽

10.1530/eje.0.1430015 ◽

2000 ◽

pp. 15-24 ◽

Cited By ~ 44

Author(s):

C Schmutzler ◽

J Koehrle

Keyword(s):

Gene Therapy ◽

Immune Response ◽

Thyroid Cancer ◽

Standard Procedure ◽

Interleukin 2 ◽

Treatment Modalities ◽

Medullary Thyroid ◽

Thyroid Carcinomas ◽

Radioiodide Therapy ◽

Medullary Thyroid Carcinomas

Normally, thyroid cancer is a disease with a good prognosis, but about 30% of the tumours dedifferentiate and may finally develop into highly malignant anaplastic thyroid carcinomas with a mean survival time of less than 8 months. Due to the loss of thyroid-specific functions associated with dedifferentiation, these tumours are inaccessible to standard therapeutic procedures such as radioiodide therapy and thyroxine-mediated thyrotrophin suppression. Medullary thyroid carcinomas are also highly aggressive. Here, therapy is limited to surgery, and no alternative is left if patients do not respond to this standard procedure. Obviously, new approaches would be desirable. Several novel approaches are currently being tested for the treatment of thyroid cancer. Many of them utilise methods of gene therapy, but follow different strategies: (1) reintroduction of the tumour suppressor p53 into a background lacking functional p53; (2) suicide gene therapy with ganciclovir and a transduced gene for herpes simplex virus thymidine kinase controlled by the thyroglobulin promoter; (3) strengthening of the antitumour immune response by expression of an adenovirus-delivered interleukin-2 (IL-2) gene; (4) induction of an immune response by DNA vaccination against the tumour marker calcitonin; (5) transduction of the thyroid sodium/iodide transporter gene to make tissues that do not accumulate iodide treatable by radioiodide therapy; (6) blocking of the expression of the oncogene c-myc by antisense oligonucleotides. While these approaches are still tested in vitro or in animal models, first results from pilot studies concerning other novel treatment modalities are available: (7) radioimmunotherapy exploits the carcinoembryonic antigen expressed on medullary thyroid carcinomas to target a radiolabelled antibody to the tumour; and (8) retinoic acid is used for a redifferentiation therapy in the case of thyroid cancer. Hopefully, one or the other of these novel strategies may probably extend after some time the current therapeutic repertoire for thyroid cancers and provide a perspective for otherwise untreatable patients.

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