Gene Therapy for Thyroid Cancer: Current Status and Future Prospects

Christine Spitzweg; John C. Morris

Disclosures

Thyroid. 2004;14(6) 

In This Article

Abstract and Introduction

Despite multimodality treatment for thyroid cancer, including surgical resection, radioiodine therapy, thyrotropin (TSH)-suppressive thyroxine treatment, and chemotherapy/radiotherapy, survival rates have not improved over the last decades. Therefore, development and evaluation of novel treatment strategies, including gene therapy, are urgently needed. A variety of gene therapy approaches have been evaluated for the treatment of follicular cell-derived and medullary thyroid cancer, including corrective gene therapy (p53 restoration, expression of a dominant negative RET mutant), cytoreductive gene therapy (suicide gene/prodrug strategy herpes simplex virus-thymidine kinase [HSV-tk]/ganciclovir, antiangiogenic therapy with endostatin) and immunomodulatory gene therapy (expression of interleukin (IL)-2 and IL-12). Furthermore, cloning of the sodium iodide symporter (NIS) gene has paved the way for the development of a novel cytoreductive gene therapy strategy based on NIS gene transfer followed by the application of radioiodine therapy (131I). NIS gene delivery into medullary and follicular cell-derived thyroid cancer cells has been shown to be capable of establishing or restoring radioiodine accumulation and might therefore represent an effective therapy for medullary and dedifferentiated thyroid tumors that lack iodide accumulating activity. The data summarized in this review article clearly demonstrate that the currently available strategies represent potentially curative novel therapeutic approaches for future gene therapy of thyroid cancer. The combination of different therapeutic genes has been demonstrated to be very useful to enhance therapeutic efficacy and seems to have a promising role at least as part of a multimodality approach for advanced thyroid cancer.

Thyroid carcinoma represents the most common endocrine malignancy, accounting for the majority of deaths from endocrine cancers. The vast majority of thyroid carcinomas (94%) are papillary and follicular thyroid carcinomas, differentiated tumors derived from follicular epithelial cells. Five percent of thyroid carcinomas are medullary thyroid carcinomas, which arise from C cells, and the remaining 1% consists of anaplastic and poorly differentiated thyroid carcinomas. While the overall survival rates for papillary (98%) and follicular (92%) thyroid cancer are high, the survival rate for medullary thyroid cancer is only 80% and for anaplastic cancer it is as low as 13%.[1] Despite multimodality treatment for thyroid cancer, including surgical resection, radioiodine (131I) therapy, thyrotropin (TSH)-suppressive thyroxine treatment, and chemotherapy/radiotherapy, survival rates have not improved over the last decades. Therefore, development and evaluation of novel treatment strategies, including gene therapy approaches, are urgently needed.

Gene therapy for thyroid cancer represents a new technology that, more than any currently available therapy, takes direct advantage of our new understanding of thyroid carcinogenesis at the molecular level. Gene therapy is particularly attractive for the treatment of thyroid cancer because of the possibility of selective targeting of therapeutic genes to tumor cells by application of tissue-specific promoters, such as the thyroglobulin and calcitonin promoter, thereby reducing extratumoral toxicity. In addition, with the possibility of complete thyroid hormone replacement therapy the thyroid gland represents a "dispensable" organ, which allows the clinician to pursue therapeutic strategies, including gene therapy, that might ablate normal as well as malignant thyroid cells.

The term gene therapy encompasses a range of approaches (Fig. 1), such as:

  • Corrective gene therapy: to restore the normal function of a deleted or mutated gene (usually a tumor suppressor gene) or negate the effect of a tumor-promoting gene (oncogene).

  • Cytoreductive gene therapy: to deliver an exogenous gene that causes cell death or allows the application of toxic agents.

  • Immunomodulatory gene therapy: to induce gene expression that enhances immune responses against tumor tissues.

Overview of gene therapeutic approaches for thyroid cancer.

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