Therapy Analysis - Telomerase as a potential therapeutic target
A diagnostic and prognostic target
...Several studies have demonstrated a correlation between clinical outcome and expression of telomerase in certain cancers...Cancer diagnostics currently apply only to a single or limited number of cancer types, as they rely on molecules expressed only by specific cancer types. However, telomerase-detectionbased diagnostics could potentially address a broad range of cancers. A highly sensitive PCR-based technique known as the telomeric repeat amplification protocol (TRAP) assay allows telomerase activity to be easily quantified in human cancer cells. Not only has positive telomerase expression been detected in many human cancers by this method, but increases in telomerase levels with concomitant progression in the severity of histopathological change have also been observed. Assays using real-time quantitative reverse transcriptase PCR have revealed a link between hTERT mRNA levels and the malignancy of breast tumours.
Several studies have demonstrated a correlation between clinical outcome and expression of telomerase in certain cancers. High levels of the enzyme in neuroblastoma and gastric cancers have been shown to indicate a poor clinical outcome, whereas some patients with tumours not expressing telomerase have experienced spontaneous regression. These data could be utilized in predicting the development of the disease, and in making decisions on treatment options dependent on the estimated threat to the patient.
However, other studies with variations to the TRAP protocol have not shown a correlation between telomerase activity and relapse-free survival in breast cancer patients. Telomerase activation may occur after the selection of mutations that stimulate abnormal cell proliferation, and thus telomerase activation may be a relatively late event in tumour development that allows for genome stability after cells gain cancer-associated mutations.
It has been argued that because hTERT expression is observable at early stages of dysplasia, telomere shortening and selection for telomerase activation may occur before critical mutations are also gained for truly malignant growth. Alternatively spliced, post-translationally modified, or catalytically inactive forms of hTERT have been reported, which may also be detected by PCR assays. Clearly, controversy still exists over the role of telomerase in a tumour cell's path to malignancy, and this is reflected in cautious development regimes by a select few specialist developers.
