Viral Mediated Gene Therapy for the Management of Metastatic Thyroid Carcinoma

Leslie   J.   DeGroot; Rusheng      Zhang

Abstract

Thyroid cancers are of special interest in gene therapy, since it is possible to direct gene expression specifically to the thyroid derived cells by using promoters with limited expression, and secondly, because destruction of the normal tissue by introduction of a toxic gene would have no important adverse effect. A variety of methods for gene delivery are available. Adenovirus is a well studied and widely used vector and is useful for targeting genes because it infects many cell types, including differentiated thyroid cancer and medullary thyroid cancer cells. Strategies that have been employed successfully in animal models include adenoviral mediated expression of thymidine kinase under control of a thyroglobulin promoter, similarly expression of the cytokine IL-2, and perhaps most effectively, expression of IL-12. Combinations of vectors expressing thymidine kinase and IL-12 under control of a strong but non-tissue specific CMV promoter effectively destroy a model anaplastic thyroid tumor in Wistar rats. Replicating adenoviruses, in contrast to the non-replicating form commonly used, have also been used to infect tumor cells and express P-53 protein, leading to apoptosis of tumor cells. Medullary thyroid cancer provides a target much like differentiated thyroid cancer because it is possible to address gene expression specifically to the medullary thyroid cells by the use of a modified calcitonin promoter. Animal models of this tumor are available in a mouse and Wag / Rij rat model. In the latter system, treatment with adenoviruses expressing genes under control of the modified calcitonin promoter and expressing thymidine kinase or IL-12 leads to destruction of growing medullary thyroid cancer tumors, destroy distant tumors after injection in one tumor, and cause induction of long lasting immunity to subsequent tumor development in the animals. There are many ongoing studies of gene therapy in humans using various genes such as thymidine kinase, IL-2, and now IL-12. Although none of these trials to date shows complete eradication of metastatic tumors in humans, there are reports showing distinctly that the viral mediated gene therapy approach can effectively destroy human tumors after in vivo administration. Tumors that have been treated include melanomas, glioblastomas, breast tumors, and prostate carcinomas. In the latter studies, it has been possible to show objective responses documented by a fall in serum PSA levels of 50% or more that are sustained for prolonged periods. Gene therapy using the adenoviral vectors appears to be safe in studies reported so far. A problem is prior or induced immunity to adenoviral proteins, but direct injection of the vector into a tumor nodule largely circumvents this problem. New genes and new vectors under development will certainly lead to the established use of these methods in the therapy of human thyroid carcinomas in the near future.

Keywords: gene therapy, metastatic thyroid carcinoma, toxic gene, thymidine kinase, thyroglobulin promoter, wag/rij rat model., melanomas, glioblastomas, breast tumors, prostate carcinomas