Evaluation of telomerase activity and telomerase inhibitors in Head and Neck cancer

Abstract

Cancer is a major cause of morbidity and mortality with increasing incidence worldwide. Early detection of cancers and better treatments would improve the outcome for patients. The overall 5-year survival rates of head and neck squamous cell carcinoma have not improved in the past several decades due to diagnosis at advanced stages and recurrent disease. Early detection and improved chemotherapy drugs are two key areas that are required to help to improve the prognosis for this disease. This thesis focuses on the enzyme telomerase which is known to contribute to one of the hallmarks of cancer (immortality). Elevated telomerase activity has been observed in the majority of cancer cells but not in most normal human cells so there is an opportunity to use telomerase as a biomarker for disease. This first part of this study assessed telomerase activity in saliva and tissues of head and neck squamous cell cancer patients. The Telomerase PCR-ELISA kit was used to assess telomerase activity in the saliva of patients with confirmed oral carcinomas and its expression was analysed in paraffin embedded tissue using immunohistochemistry (IHC). Whilst telomerase was detected in cell lines, no telomerase activity was detected in saliva samples from patients but was detectable in IHC specimens. The second part of the study focused on the pharmacological evaluation of a series of small molecule G–quadruplex DNA binding agents as potential telomerase inhibitors. A total of 19 telomerase inhibitors were identified but of these, only 4 were specific inhibitors of telomerase. These compounds also caused toxicity to cell lines following a 2 hour drug exposure at doses that also inhibit telomerase activity. Further studies are required to explore these compounds further. In conclusion, the results of this study have demonstrated that detection of telomerase activity I the saliva of patients with oral cancers is unlikely to be useful in terms of detecting oral cancers before symptoms of the disease are clinically manifest. A series of novel and specific inhibitors of telomerase have been identified and further studies are required to develop these compounds further.