IMPROVING RADIOIODINE TREATMENT OF THYROID AND OTHER TUMOURS

A main treatment option for thyroid cancer, and a potential therapeutic strategy in breast and prostate cancer, is radioactive iodide, which is concentrated in the cell, and then kills cancer cells. One problem with this is that the protein NIS which helps 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 a protein called PBF drastically reduces the ability of NIS to function. We therefore want to explore how we can overcome this effect, particularly because thyroid cancers have high levels of PBF, and breast and prostate cancers can be engineered to express functional levels of NIS. If we can prevent PBF from reducing NIS activity, we may restore radioactive iodide uptake. This should directly improve therapy and outcome, particularly for the subset of patients who are currently very difficult to treat, and who have less than a 50% chance of surviving 5 years with thyroid cancer. Also, given that PBF is highly expressed in other cancers, changing the way that PBF affects NIS would have further potential in the treatment of breast and prostate cancers.

Our recent unpublished data reveal a potential therapeutic strategy for overcoming the potent repression which PBF exerts on the sodium iodide symporter, NIS. We show that PBF is tyrosine phosphorylated at residue Y174, and that abrogation of this residue prevents PBF binding NIS. Since PBF is a protein which interacts with NIS, alters NIS subcellular localisation and governs NIS activity, phosphorylation of PBF thus represents a direct therapeutic opportunity in the restoration of iodide uptake which no other group is pursuing. We will investigate the precise mechanism by which PBF represses NIS activity in vitro, using our recently developed phospho-specific antibody to PBF. Through the use of the human kinome siRNA library, as well as an expression screen using a cDNA expression library of all known kinases and phosphatases, we will identify the kinase(s) responsible for phosphorylating PBF. In parallel, we will evaluate a tyrosine kinase inhibitor (TKI) library to identify a TKI capable of ameliorating PBF phosphorylation. Subsequently, we will modulate tyrosine phosphorylation of PBF in vitro and in vivo. We will utilise our recently constructed transgenic mouse model of thyroid-specific PBF over-expression, as well as human thyroid cell lines and human thyroid tumour samples. An orthotopic model of murine thyroid cancer, coupled with iodide uptake and ablation experiments, will provide a final proof of principle. Our ultimate experimental goal is to overcome PBF's inhibition of NIS and hence exploit the innate ability of thyroid cells to concentrate radioiodine. This would have clear clinical impact in the treatment of recurrent and metastatic thyroid disease, where prognosis is poor, and other currently available therapeutic avenues are largely ineffective.

Differentiated thyroid cancer (DTC) accounts for ~90% of all endocrine tumours, and its incidence is rapidly rising, being currently the 8th most prevalent tumour type. Most thyroid carcinomas have a good prognosis, but up to 30% recur. Treatment with radioiodine is mediated via the sodium iodide symporter (NIS). Most differentiated tumours have repressed NIS expression, and approximately 10-20 % do not express NIS despite TSH stimulation. These tumours are associated with a poor therapeutic response, and consequently a poor prognosis. Further, metastasis occurs in around 10% of cases overall, and half of these subjects are refractory to radioactive iodine treatment, with a 10-year survival rate of just 10-20%. Of particular clinical relevance are our recent findings that the protein PBF represses NIS expression and function, thereby inevitably affecting the treatment of thyroid diseases with radioiodine. PBF is induced in thyroid and other cancers, and its expression correlates with early recurrence. Given the prevalence of radioiodine treatment, and that NIS is being increasingly investigated as a therapeutic tool in non-thyroidal tumours, such as breast and prostate, understanding the mechanisms of its repression is of critical clinical importance both to present and future ablative radioiodine treatment.
Thus, if successful, our work will have several strands of direct beneficiary. We will hope to impact upon NHS policy makers, providing compelling data that short-term treatment (24 hours) with an established and well tolerated tyrosine kinase inhibitor, or else a specific monoclonal antibody to PBF, will result in an increased efficacy of radioiodine treatment for patients with thyroid cancer. This will clearly require testing through clinical trials, but particularly in the case of a well known TKI, should elicit direct outcome data without confounding drug toxicity issues. Should radioiodine treatment efficacy be improved there will be a clear health and thus wealth benefit, given that patients will show a lower incidence of tumour recurrence and clinical complexities involved in metastatic thyroid disease. To make this commercially viable and beneficial to the UK, our collaboration with MRC Technology will seek to identify specific TKIs which alter PBF function and which are not currently in routine clinical use, which MRC Technology has proprietary ownership of.
In the case of the monoclonal antibody to PBF which we will generate in this project, given successful amelioration of PBF repression of iodide uptake in our murine model, or intention would be to develop this as a novel therapeutic strategy in its own right.
If we can effectively alter the uptake of radioiodine via our TKI or monoclonal antibody approaches, there may be a less immediate impact upon strategies to use radioiodine treatment in breast and prostate cancer. Given the high prevalence rates of both tumour types, it is conceivable that there would be a large beneficial impact both clinically and financially of being able to attack breast and prostate cancer with safe and highly effective radioiodine treatment.