New mechanisms of sodium iodide Symporter Repression
Lead Research Organisation:
University of Birmingham
Department Name: Clinical and Experimental Medicine
Abstract
Thyroid cancer is relatively common, and growing in incidence. A main treatment option for thyroid cancer is radioactive iodide, which is concentrated in the thyroid, and then kills cancer cells. One problem with this is that the protein NIS which helps thyroid cells take up the radioactive iodide is not as active in cancer cells as it is in normal cells. This means that the treatment is not as effective as it could be. We are aiming to change this.
We have discovered that two genes called PTTG and PBF reduce the ability of the NIS to function. We therefore want to explore how we can overcome this effect, particularly because thyroid and other cancers have high levels of PTTG and PBF. If we can prevent PTTG and PBF from stopping NIS uptaking radioactive iodide, this should improve therapy and mean that this treatment might also work better in other cancers in which radioactive iodide is being tested.
We have discovered that two genes called PTTG and PBF reduce the ability of the NIS to function. We therefore want to explore how we can overcome this effect, particularly because thyroid and other cancers have high levels of PTTG and PBF. If we can prevent PTTG and PBF from stopping NIS uptaking radioactive iodide, this should improve therapy and mean that this treatment might also work better in other cancers in which radioactive iodide is being tested.
Technical Summary
The sodium iodide symporter (NIS) offers the unique potential of being both a diagnostic and a therapeutic gene: It is possible to image, monitor and treat tumours by exploiting NIS mediated uptake of radioiodide. Advances in understanding the factors which regulate the NIS gene have profound implications for the treatment of thyroid tumours, as well as breast cancer and other non-thyroidal tumours currently being assessed for NIS-mediated therapy. We have recently discovered that pituitary tumor transforming gene (PTTG) and its binding factor (PBF) inhibit NIS activity in vitro, and have mapped the promoter elements responsible. PTTG and PBF are over-expressed in thyroid and other tumours, and high expression of both genes in thyroid cancer is associated with aggressive tumour behaviour. We now intend to explore this novel link between two proto-oncogenes and a critical symporter protein through a variety of approaches.
Our central model will be human primary thyroid cells, which actively uptake iodide, are easily transfectable and express relatively low endogenous levels of PTTG and PBF. We will seek to understand the exact mechanisms of repression, to investigate ways of overcoming this repression and to extrapolate our findings to non-thyroidal cells. Our hypothesis is that amelioration of PTTG and PBF repression of NIS activity in patients with high expression of these two oncogenes will increase the efficacy of radioiodide treatment, both in thyroid tumours and in non-thyroidal cancers where NIS may be used for ablative therapy.
Our central model will be human primary thyroid cells, which actively uptake iodide, are easily transfectable and express relatively low endogenous levels of PTTG and PBF. We will seek to understand the exact mechanisms of repression, to investigate ways of overcoming this repression and to extrapolate our findings to non-thyroidal cells. Our hypothesis is that amelioration of PTTG and PBF repression of NIS activity in patients with high expression of these two oncogenes will increase the efficacy of radioiodide treatment, both in thyroid tumours and in non-thyroidal cancers where NIS may be used for ablative therapy.